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Current and Emerging Strategies in Bladder Cancer
Simone Carradori, Cristiano Cristini, Daniela Secci, Caterina Gulia, Vincenzo Gentile and Giovanni Battista Di Pierro
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00053]


Recent Developments of Small Molecule EGFR Inhibitors Based on the Quinazoline Core Scaffolds
Yu-Jing Liu, Cheng-Mei Zhang and Zhao-Peng Liu
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00054]


Downregulation of Hypoxia-related Responses by Novel Antitumor Histone Deacetylase Inhibitors in MDAMB231 Breast Cancer Cells
Antonella Naldini, Irene Filippi, Elena Cini,  Manuela Rodriquez, Fabio Carraro and Maurizio Taddei
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00056]


Chemoinformatics in Multi-Target Drug Discovery for Anti-Cancer Therapy: In Silico Design Of Potent And Versatile Anti-Brain Tumor Agents
Alejandro Speck-Planche, Valeria V. Kleandrova, Feng Luan  and M. Natália D. S. Cordeiro
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00058]


Cranberry as Promising Natural Source of Potential Anticancer Agents: Current Evidence and Future Perspectives
Athanasios Katsargyris, Ekaterini-Christina Tampaki, Constantinos Giaginis and Stamatios Theocharis
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00061]


Hepatocarcinogenesis And Ceramide/Cholesterol Metabolism
Albert Morales, Montserrat Marí, Carmen García-Ruiz, Anna Colell and Jose C. Fernández-Checa
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00062]


Cdk1 Hyperphosphorylation Maintenance Drives The Time-Course Of G2-M Cell Cycle Arrest After Short Treatment With Nami-A In Kb Cells
Alberta Bergamo, Riccarda Delfino, Claudia Casarsa and Gianni Savaa
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00071]


Genistein potentiates the anti-cancer effects of gemcitabine in human osteosarcoma via the downregulation of Akt and nuclear factor-κB pathway
Chengzhen Liang, Hao Li, Chengchun Shen, Jianbo Lai, Zhongli Shi, Bing Liu and Hui-min Tao
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00072]


AnticancerActivity and Anti-inflammatory studies of 5-Aryl-1,4-benzodiazepine Derivatives
Cortez-Maya Sandra, Cortés Cortés Eduardo, Hernández-Ortega Simón, Ramírez Apan Teresa, Nieto Camacho Antonio, Irina V. Lijanova and Martínez-García Marcos
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00073]


Neutrophil Elastase as a Target in Lung Cancer
Gautier Moroy, Alain J.P. ALIX, Janos SAPI, William Hornebeck and Erika Bourguet
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00074]


Effects of bioactive compounds from carrots (Daucus carota L.), polyacetylenes, beta-carotene and lutein on human lymphoid leukaemia cells
Rana G. Zaini, Kirsten Brandt, Malcolm R. Clench and Christine L. Le Maitre
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00075]


The cytotoxic effect of emetine and CGP-74514A studied with the Hollow Fiber Model and ArrayScan Assay in neuroendocrine tumors In Vitro
Dhana E. Larsson, Saadia B. Hassan, Kjell Öberg and Dan Granberg
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00076]


Anticancer Effects of the Organosilicon Multidrug Resistance Modulator SILA 421
Ulrike Olszewski-Hamilton, Robert Zeillinger, Meltem Demirel Kars, Attila Zalatnai, Jozsef Molnar and Gerhard Hamilton
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00077]


Differential expressions of matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs and their endogenous inhibitors among histologic subtypes of lung cancers
Yasuhiro Hida and Jun-ichi Hamada
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00078]


Triple-negative breast cancer and Poly(ADP-ribose) polymerase inhibitors
Youngjin Park, Ayako Moriyama, Tomoaki Kitahara, Yutaka Yoshida, Tasuku Urita and Ryoji Kato
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00079]


Gallium phthalocyanine photosensitizers: carboxylation enhances the cellular uptake and improves the photodynamic therapy of cancers
Jin F. Zhao, Jing Wang, Ji-Yao Chen, Wadzanai Chidawanykia, T. Nyokong, Kazuyuki Ishii, N and Kobayashi
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00080]


A new 4-phenyl-1,8-naphthyridine derivative affects carcinoma cell proliferation by impairing cell cycle progression and inducing apoptosis
Antonella Capozzi, Elisabetta Mantuano, Paola Matarrese, Giuseppe Saccomanni, Clementina Manera, Vincenzo Mattei, Lucrezia Gambardella, Walter Malorni, Maurizio Sorice and Roberta Misasi
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00082]


The role of Cdc25A in the regulation of cell proliferation and apoptosis
Tao Shen and Shile Huang
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00083]


Boronated Compounds for Imaging Guided BNCT Applications
Simonetta Geninatti-Crich, Annamaria Deagostino, Antonio Toppino, Diego Alberti, Paolo Venturello and Silvio Aime
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00084]


Design of N-substituted aminobutyric hydroxamic acid histone deacetylase inhibitors reveal an essential role for cap atomic composition
Jean Michel Brunel, Chanaz Salmi-Smail, Audrey Restouin, Thomas Prébet, Norbert Vey and Yves Collette
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00085]


Pro-apoptotic Activity of BH3-only Proteins and BH3 Mimetics: from Theory to Potential Cancer Therapy
Mariusz L. Hartman and Malgorzata Czyz
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00086]


Antiangiogenic drugs in the treatment of advanced epithelial ovarian cancer
Parham Khosravi-Shahi and Luis Cabezón-Gutiérrez
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00087]


A novel fusicoccin derivative preferentially targets hypoxic tumor cells and inhibits tumor growth in xenografts
Koshi Kawakami, Miho Hattori, Takatsugu Inoue, Yuriko Maruyama, Junko Ohkanda, Nobuo Kato, Miki Tongu, Takaya Yamada, Miho Akimoto, Keizo Takenaga, Takeshi Sassa, Junji Suzumiya and Yoshio Honma
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00088]


Modulation Of Mmps By Cell Surface Integrin Receptor α5β1
Sekhar Pal, Kirat Kumar Ganguly, Shuvojit Moulik and  Amitava Chatterjee
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00091]


Inhibiting Matrix Metalloproteinases, An Old Story With New Potentials For Cancer Treatment
Dimitris Stellas and Evangelia Patsavoudi
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00092]


Regulation Of Mmps During Melanoma Progression: From Genetic To Epigenetic
Antonicelli Frank, Vallerand David, Trussardi-Regnier Aurélie, Grange Florent, Hornebeck William and Bernard Philippe
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00093]


Micrornas In Cancer: Small Molecules, Big Chances
Mohammed Abba, Giridhar Mudduluru and Heike Allgayer
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00094]


Novel Strategies for Hepatocellular Carcinoma Based on MMPs Science
Isao Okazaki and Yutaka Inagaki
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00095]


Introduction: MMPs, ADAMs/ADAMTSs Research Products To Achieve Big Dream
Isao Okazaki and Kazuki Nabeshima
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00096]


MMPs in Ovarian Cancer as Therapeutic Targets
Amer Karam and Oliver Dorigo
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00097]


RECKing MMP: Relevance of Reversion-inducing Cysteine-rich Protein with Kazal Motifs as a Prognostic Marker and Therapeutic Target for Cancer (A Review)
Siddavaram Nagini
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00098]


Differential Expressions Of Matrix Metalloproteinases, A Disintegrin And Metalloproteinases, And A Disintegrin And Metalloproteinases With Thrombospondin Motifs And Their Endogenous Inhibitors Among Histologic Subtypes Of Lung Cancers
Yasuhiro Hida and Jun-ichi Hamada
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00099]


Editorial: Novel Cancer-targeting Agents/Application Strategies Developed from MMP Science

Guest Editor:

Isao Okazaki
Department of Internal Medicine, Sanno Hospital,
International University of Health and Welfare,
8-10-16 Akasaka, Minato-ku,
Tokyo 107-0052,
Japan
Tel: +81-3-3402-3151; Fax: +81-3-3404-3652
E-mail: iokazaki@iuhw.ac.jp
[BSP/ACAMC/E-Pub/00100]


Editorial: Peptide-Receptor Ligands In Imaging And Therapy Of Cancer

Guest Editor:

Paolo Ruzza
Institute of Biomolecular Chemistry of CNR, Padova Unit
via Marzolo 1
35131 Padova, Italy
Phone: +39 049 827 5282
Fax: +39 049 827 5239
Email:paolo.ruzza@unipd.it; paolo.ruzza@cnr.it
[BSP/ACAMC/E-Pub/00101]


Chelating Systems for ^99mTc/¹⁸⁸Re in the development of Radiolabeled Peptide Pharmaceuticals
Cristina Bolzati, Davide Carta, Nicola Salvarese and Fiorenzo Refosco
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00102]


Peptide Receptor Radionuclide Therapy With Somatostatin Analogues In Neuroendocrine Tumors
Giampiero Giovacchini, Guillaume Nicolas and Flavio Forrer
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00103]


Optical and Multimodal Peptide-Based Probes For In Vivo Molecular Imaging
Laura Melendez-Alafort, Pier Carlo Muzzio and Antonio Rosato
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00104]


Drug Targeting Strategies for Photodynamic Therapy
Frédéric Schmitt and Lucienne Juillerat-Jeanneret
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00105]


Peptide-Receptor Ligands And Multivalent Approach
Paolo Ruzza, Anna Marchiani, Nicola Antolini and Andrea Calderan
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00106]


Molecular Imaging of Cancer with Radiolabeled Peptides and PET
Amy L. Vāvere and Raffaella Rossin
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00107]


Flavonoids In Cancer Prevention
Eun-Jung Park and John M. Pezzuto
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00108]


Regulation of Cell Death And Survival By Resveratrol: Implications For Cancer Therapy
Simone Fulda
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00109]


Targeting Tumor Ubiquitin-Proteasome Pathway with Polyphenols for Chemosensitization
Min Shen, Tak Hang Chan and Q. Ping Dou
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00110]


Natural-derived Polyphenols as Potential Anticancer Agents
Carmela Spatafora and Corrado Tringali
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00111]


Structures Required Of Flavonoids For Inhibiting Digestive Enzymes
Hui Cao and Xiaoqing Chen
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00112]


Probing the Interaction of Anti-cancer agent Dihydromyricetin with Human Serum Albumin: A typical method study
Tingting Chen, Shajun Zhu, Yapeng Lu, Yu Zhao, Guoqing Jiang, Li Zhu and Tianhong Lu
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00113]


Immunomodulation And Anti-Inflammatory Roles Of Polyphenols As Anticancer Agents
François Ghiringhelli, Cédric Rébé, Aziz Hichami and Dominique Delmas
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00114]


Bovine Serum Albumin Significantly Improves The DPPH Free Radical Scavenging Potential Of Dietary Polyphenols And Gallic Acids
Hui Cao, Xiaoqing Chen and Koichiro Yamamoto
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00115]


A Small-Molecule Inhibitor, 5′-O-Tritylthymidine, Targets FAK And Mdm-2 Interaction, And Blocks Breast And Colon Tumorigenesis In Vivo
Vita Golubovskaya, Nadia L. Palma, Min Zheng, Baotran Ho, Andrew Magis, David Ostrov and William G. Cance
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00116]


Mitoxantrone Targets The ATP-Binding Site Of FAK, Binds The FAK Kinase Domain And Decreases FAK, Pyk-2, C-Src, And IGF-1R, Pyk-2 In Vitro Kinase Activities
Vita Golubovskaya, Baotran Ho, Min Zheng, Andrew Magis, David Ostrov and William Cance
[Abstract] [Purchase Article] [BSP/ACAMC/E-Pub/00117]


Anticoagulant and Fibrinolytic Drugs Possible Agents In Treatment Of Lung Cancer?
Vladimir Bobek
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00118]


In Vitro Synergistic Interaction between DTA0100 and Radiation in Human Cancer Cell Lines
Elisa Bordón, Leticia G. León, Carla Ríos-Luci, Pedro C. Lara and José M. Padrón
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00119]


Gambogic Acid Is A Novel Anti-Cancer Agent That Inhibits Cell Proliferation, Angiogenesis And Metastasis
Xu Wang and Wantao Chen
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00120]


Fig latex (Ficus carica L. cultivar Dottato) in combination with UV irradiation decreases the viability of A375 melanoma cells in vitro
Giulio Menichini, Carmine Alfano, Eugenio Provenzano, Mariangela Marrelli, Giancarlo A. Statti, Francesco Somma, Francesco Menichini and Filomena Conforti
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00121]


Methylenedioxy- and Ethylenedioxy-Fused Indolocarbazoles. Potent Human Topoisomerase I Inhibitors and Antitumor Agents
David E. Zembower, Yongping Xie, Ali Koohang, Mary J. Kuffel, Matthew M. Ames, Yasheen Zhou, Rama Mishra, Aye Aye Mar, Michael T. Flavin and Ze-Qi Xu
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00122]


Doxorubicin-Loaded Nanoparticles: New Advances in Breast Cancer Therapy
J. Prados, C. Melguizo, R. Ortiz, C. Vélez, P.J. Alvarez, J.L. Arias, M.A. Ruíz, V. Gallardo and A. Aranega
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00123]


Polyphenols counteract tumor cell chemoresistance conferred by multidrug resistance proteins
Krystyna Michalak and Olga Wesołowska
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00126]


Editorial: Natural Polyphenols Properties: Chemopreventive and Chemosensitizing Activities
Dominique Delmas and Jianbo Xiao
[BSP/ACAMC/E-Pub/00127]


Editorial: Natural Compounds as Cancer Chemopreventive and Chemotherapeutic Agents: Insights Gained from Mechanistic and Pharmacologic Studies
Bao Ting Zhu
[BSP/ACAMC/E-Pub/00128]


Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets
Poyil Pratheeshkumar, Chakkenchath Sreekala, Zhuo Zhang, Amit Budhraja, Songze Ding, Young-Ok Son, Xin Wang, Andrew Hitron, Kim Hyun-Jung, , Lei Wang, Jeong-Chae Lee and Xianglin Shi
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00129]


Chemoprevention of Breast Cancer By Dietary Compounds
Aditi Shirish Vadodkar, Suman Suman, Rajkumar Lakshmanaswamy and Chendil Damodaran
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00130]


Unifying Mechanisms of Action of the Anticancer Activities of Triterpenoids and Synthetic Analogs
Stephen H. Safe, Paul L. Prather, Lisa K. Brents, Gayathri Chadalapaka and Indira Jutooru
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00131]


Anti-cancer and Other Bioactivities of Korean Angelica gigas Nakai (AGN) and Its Major Pyranocoumarin Compounds
Jinhui Zhang, Li Li, Cheng Jiang, Chengguo Xing, Sung-Hoon Kim and Junxuan Lü
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00132]


The Cancer Preventive Effects of Edible Mushrooms
Tongtong Xu, Robert B. Beelman and Joshua D. Lambert
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00133]


Bioavailability and Pharmacokinetics of Genistein: Mechanistic Studies on its ADME
Zhen Yang, Kaustubh Kulkarni, Wei Zhu and Ming Hu
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00134]


Plants against Cancer: A Review on Natural Phytochemicals in Preventing and Treating Cancers and Their Drug ability
Hu Wang, Tin Oo Khor, Limin Shu, Zhengyuen Su, Francisco Fuentes and Jong-Hun Lee
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00135]


Developing Phytoestrogens for Breast Cancer Prevention
Mandy M. Liu, Ying Huang and Jeffrey Wang
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00136]


Prevention of Colitis-associated Cancer: Natural Compounds that target the IL-6 Soluble Receptor
Cate Moriasi, Dharmalingam Subramaniam, Shanjana Awasthi, Satish Ramalingam and Shrikant Anant
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00137]


The Nuclear Orphan Receptors Nr4a As Therapeutic Target In Cancer Therapy
Alexander J. A. Deutsch, Hannes Angerer, Tamara E. Fuchs and Peter Neumeister
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00138]


Calculation of Molecular Features with Apparent Impact on Both Activity Of Mutagens And Activity Of Anticancer Agents
Andrey A. Toropov, Alla P. Toropova, Emilio Benfenati, Giusippina Gini, Danuta Leszczynska and Jerzy Leszczynski
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00139]


Anti-Metastatic and Anti-Angiogenic Properties Of Potential New Anti-Cancer Drugs Based on Metal Complexes Of Selenosemicarbazones
Manja Zec, Tatjana Srdic-Rajic, Aleksandra Konic-Ristic, Tamara Todorovic, Katarina Andjelkovic, Ivana Filipovic-Ljeskovic and Sinisa Radulovic
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00140]


The Role of Peroxisome Proliferator-Activated Receptor-γ in Breast Cancer
Ioly Kotta-Loizou, Constantinos Giaginis and Stamatios Theocharis
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00141]


Dual Roles of Sulforaphane in Cancer Treatment
Tongzhen Xu, Dongmei Ren, Xuefei Sun and Guotao Yang
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00142]


Colon Adenocarcinoma Multidrug Resistance Reverted by Euphorbia Diterpenes: Structure-Activity Relationships and Pharmacophore Modeling
Mariana Reis, Ricardo J. Ferreira, Julianna Serly, Noélia Duarte, Ana M. Madureira, Daniel J. V. A. Santos, Joséph Molnár and Maria-José U. Ferreira
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00143]


CCR5 as a potential target in cancer therapy: inhibition or stimulation?
Alicia González-Martín, Emilia Mira and Santos Mañes
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00144]


Targeted therapy for advanced urothelial cancer of the bladder: Where do we stand?
Zhaowei Zhu, Zhoujun Shen and Chen Xu
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00145]


Experimental and Theoretical Advances in Functional Understanding of Flavonoids as Anti-Tumor Agents
B. Venkata Babu, Naveen Kumar Konduru, Waro Nakanishi, Satoko Hayashi, Naseem Ahmed and Petar M. Mitrasinovic
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00146]


Platinum Compounds: A Hope for Future Cancer Chemotherapy
Imran Ali, Waseem A. Wani, Kishwar Saleem and Ashanul Haque
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00147]


Treatment Directed To Signalling Molecules In Patients With Advanced Differentiated Thyroid Cancer
José Manuel Gómez Sáez
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00148]


Rational Drug Design For Identifying Novel Multi-target Inhibitors For Hepatocellular Carcinoma
Ahmed Temirak, Mona Abdulla and Mahmoud Elhefnawi
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00149]


Metformin: A Rising Star to Fight the Mesenchymal Epithelial Transition In Oncology
Guislaine Barrière, Michel Tartary and Michel Rigaud
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00150]


JAK2 Inhibitors for Myelofibrosis: Why Are They Effective in Patients With and Without JAK2V617F Mutation?
Fabio P S Santos and Srdan Verstovsek
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00151]


Anti-Cancer Effects of Curcumin On Head And Neck Cancers
Wei Gao, Jimmy Yu-Wai Chan, William Ignance Wei and Thian-Sze Wong
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00152]


Cytoskeletal Alterations That Confer Resistance to Anti-Tubulin Chemotherapeutics
Arun Kanakkanthara, Paul H. Teesdale-Spittle and John H. Miller
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00153]


Anticancer Activity of New Haloalkyl Camptothecin Esters against Human Cancer Cell Lines and Human Tumor Xenografts Grown in Nude Mice
Zhisong Cao, John Mendoza, Anthony Kozielski, Xing Liu, Albert DeJesus, Yang Wang, Chang-Guo Zhan, Dana Vardeman and Beppino Giovanella
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00154]



Abstracts

Current and Emerging Strategies in Bladder Cancer
Simone Carradori, Cristiano Cristini, Daniela Secci, Caterina Gulia, Vincenzo Gentile and Giovanni Battista Di Pierro
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00053]

Urothelial cell carcinoma is one of the most common malignancies of the urinary tract. The standard of care, intravesical chemo- and immunotherapy, while effective, is associated with a considerable side-effect profile and approximately 30% of patients either fail to respond to treatment or suffer recurrent disease within 5 years. In the setting of muscle-invasive urothelial carcinoma, use of neoadjuvant chemotherapy is associated with overall survival benefit. Muscle invasive bladder cancer is life threatening, showing modest chemosensitivity, and usually requires radical cystectomy. Although bladder cancer is fairly well-genetically characterized, clinical trials with molecularly targeted agents have, in comparison to other solid tumors, been few in number and largely unsuccessful. Hence, bladder cancer represents a considerable opportunity and challenge for alternative therapies. In this review, we will focus on promising global or pathway-based approaches (epigenetic modulators, kinase inhibitors, angiogenesis blockage, peroxisome proliferator-activated receptor γ agonists, apoptosis inductors, virus therapy) supported by a deeper understanding of molecular biology of urothelial carcinoma, which have been recently tested in clinical trials.
[Back to top]


Recent Developments of Small Molecule EGFR Inhibitors Based on the Quinazoline Core Scaffolds
Yu-Jing Liu, Cheng-Mei Zhang and Zhao-Peng Liu
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00054]

Progress in identifying and understanding the molecular and cellular causes of cancer has led to the discovery of anomalies that characterize cancer cells and that represent targets for the development of cancer therapeutics. One such target is the epidermal growth factor receptor (EGFR), a transmembrane protein that is frequently dysregulated in cancer cells and associated with the development, progression and aggressiveness of a number of malignancies. Inhibition of EGFR signaling has thus been identified as an attractive strategy in control of tumor proliferation, and over a decade of intense activity in the field has culminated in the discoveries and subsequent approvals of gefitinib and erlotinib for the treatment of non-small cell lung cancer. However, the drug’s resistance to gefitinib and erlotinib has been clinically observed. Therefore, intensive efforts have been made in the discovery of novel potent and selective EGFR inhibitors. This review will focus on the developments of small molecule EGFR inhibitors based on the quinazoline core scaffolds in recent 5 years. Diverse EGFR inhibitors are classified as 4-anilinoquinazolines and 4-nonanilininoquinazolines, their biological data are described, and the structure-activity relationships (SARs) are discussed.
[Back to top]


Downregulation of Hypoxia-related Responses by Novel Antitumor Histone Deacetylase Inhibitors in MDAMB231 Breast Cancer Cells
Antonella Naldini, Irene Filippi, Elena Cini,  Manuela Rodriquez, Fabio Carraro and Maurizio Taddei
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00056]

The tumour microenvironment is characterized by a poor circulation which results in selection of neoplastic cells that can grow or survive under hypoxic conditions. The relationship between hypoxia and histone deacetylase (HDAC) inhibitors has been previously established. In this work we evaluated the effects of novel HDAC inhibitors (the natural peptide FR235222 and three tetrapeptide analogues) in the human breast cancer cell line MDAMB231, cultured under hypoxia (2% O₂ ≈ 14 mmHg) or normoxia (20% O₂ ≈ 140 mmHg).

First, we found that the novel HDAC inhibitors reduced cell proliferation in MDAMB231 cells at an extent which was similar or even higher than that exerted by the classic HDAC inhibitors trichostatin-A and suberoylanilide hydroxamic acid. More interestingly, the antiproliferative effects of the novel HDAC inhibitors were, in general, significantly higher in hypoxic cells than in normoxic controls. Hypoxic MDAMB231 cells expressed high levels of the hypoxia-inducible factor (HIF)-1α and HIF-1α-related genes, such as vascular endothelial growth factor, Bcl-2/E1B 19 kDa interacting protein-3, glucose transporter-1, carbonic anhydrase IX, as determined by Western blot analysis and qRT-PCR. Finally, we found that HIF-1α and HIF-1α-related genes were significantly downregulated by FR235222 and analogues. In conclusion, the identification of novel effects exerted by the HDAC inhibitors, characterized by a strong efficacy in inhibiting the expression of HIF-1α and its related genes, may have important implications in the pharmacological control of several tumours, including breast cancer, characterized by the presence of hypoxia, angiogenesis and metabolic derangements.
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Chemoinformatics in Multi-Target Drug Discovery for Anti-Cancer Therapy: In Silico Design Of Potent And Versatile Anti-Brain Tumor Agents
Alejandro Speck-Planche, Valeria V. Kleandrova, Feng Luan  and M. Natália D. S. Cordeiro
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00058]

A brain tumor (BT) constitutes a neoplasm located in the brain or the central spinal canal. The number of new diagnosed cases with BT increases with the pass of the time. Understanding the biology of BT is essential for the development of novel therapeutic strategies, in order to prevent or deal with this disease. An active area for the search of new anti-BT therapies is the use of Chemoinformatics and/or Bioinformatics toward the design of new and potent anti-BT agents. The principal limitation of all these approaches is that they consider small series of structurally related compounds and/or the studies are realized for only one target like protein. The present work is an effort to overcome this problem. We introduce here the first Chemoinformatics multi-target approach for the in silico design and prediction of anti-BT agents against several cell lines. Here, a fragment-based QSAR model was developed. The model correctly classified 89.63% and 90.93% of active and inactive compounds respectively, in training series. The validation of the model was carried out by using prediction series which showed 88.00% of correct classification for active and 88.59% for inactive compounds. Some fragments were extracted from the molecules and their contributions to anti-BT activity were calculated. Several fragments were identified as potential substructural features responsible of anti-BT activity and new molecular entities designed from fragments with positive contributions were suggested as possible anti-BT agents.
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Cranberry as Promising Natural Source of Potential Anticancer Agents: Current Evidence and Future Perspectives
Athanasios Katsargyris, Ekaterini-Christina Tampaki, Constantinos Giaginis and Stamatios Theocharis
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00061]

Accumulating evidence suggest that dietary modification can lower the risk for several cancer types’ development. Cranberry in particular, has been shown to have anti-oxidative, -inflammatory and -proliferative properties in vitro. To present the latest knowledge regarding the role of cranberry extracts against human cancer several types. A review of the literature documenting both in vitro and in vivo anti-cancer effects of whole cranberry and/or its extracts isconducted; Current data provide evidence for several anti-cancer properties of either whole cranberry and/or its extracts. The discovery of the specific cranberry components and the appropriate concentrations that exert such beneficial effects along with verification of the preliminary in vitro results in in vivo settings could potentially lead to the invention of novel safer and efficient anti-cancer therapeutic agents.
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Hepatocarcinogenesis And Ceramide/Cholesterol Metabolism
Albert Morales, Montserrat Marí, Carmen García-Ruiz, Anna Colell and Jose C. Fernández-Checa
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00062]

Sphingolipids (SLs) and cholesterol are critical structural components of membrane bilayers. Although recent evidence has revealed an emerging role of both lipids in signaling pathways, their contribution to cancer development and treatment has been largely overlooked. Sphingolipids comprise a family of bioactive lipids with divergent roles in numerous cellular processes. In particular, ceramide is the prototype of SLs and identified as a cell death effector whose levels increase in response to apoptotic stimuli such as ionizing radiation or chemotherapy. In the liver, ceramide/cholesterol accumulation contributes to a wide range of pathologies, including the transition from steatosis to steatohepatitis, which can further progress to cirrhosis and hepatocellular carcinoma (HCC). Moreover, different studies have shown that either pharmacologic ceramide accumulation or systemic intravenous administration of liposomal ceramide is an effective approach against HCC. In addition, mitochondrial cholesterol trafficking has emerged as a novel factor regulating cell death pathways and HCC tumor growth and chemoresistance. Due to the poor efficacy of current HCC treatments, understanding of the role of ceramide/cholesterol in HCC may open up novel avenues for therapy. Here we describe recent evidence indicating that ceramide-generating agents and/or pharmacological targeting of sphingolipid/cholesterol metabolism, alone or in combination with other chemotherapeutic compounds, may be a promising strategy in HCC management.
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The Sequence Specificity of the Anti-Tumour Drug, Cisplatin, In Telomeric DNA Sequences Compared With Consecutive Guanine DNA Sequences
Vincent Murray and Niruba Kandasamy
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00063]

The sequence specificity of the anti-tumour drug, cisplatin, was determined in a DNA sequence that contained seven telomeric repeats and a run of ten consecutive guanine bases. Cisplatin preferentially forms DNA adducts at consecutive guanine sequences. Hence these DNA sequences were examined in order to gain an insight into the important human genomic regions that are damaged by cisplatin. A polymerase stop/linear amplification assay was employed with an automated DNA capillary sequencer and laser-induced fluorescence detection to quantitatively determine the DNA sequence specificity of cisplatin in a plasmid clone containing seven telomeric repeats and a sequence of ten consecutive guanine bases. It was found that cisplatin preferentially damaged the ten consecutive guanine sequences although the telomeric DNA sequences were also a major site of cisplatin adduct formation.
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Cdk1 Hyperphosphorylation Maintenance Drives The Time-Course Of G2-M Cell Cycle Arrest After Short Treatment With Nami-A In Kb Cells
Alberta Bergamo, Riccarda Delfino, Claudia Casarsa and Gianni Savaa
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00071]

We investigated the molecular events of the ruthenium complex NAMI-A (0.1 mM for 1 h) on cell cycle G2-M arrest in KB carcinoma cells. Flow cytometry analysis showed a progressive accumulation of cells in S phase at 16 h, and in G2-M phase at 20 h after the end of treatment. NAMI-A pre-mitotic stop to cell proliferation was due to the maintenance of the phosphorylated, inactive, form of Cdk1, caused by the activation of the ATM/ATR checkpoint, as confirmed by the up-regulation and phosphorylation of Chk1. All these events are related to intracellular ruthenium accumulation, as confirmed by the lack of similar effects in cell lines unable to take the ruthenium compound up. Considering the dependence of NAMI-A cell cycle arrest on the dose and on the length of cell challenge, and considering the prolonged NAMI-A t1/2 in vivo in the lungs, we proved an even greater perturbation of the cell cycle regulating pathways in lung metastases of NAMI-A treated mice. The ex-vivo data confirm the interaction of the ruthenium compound NAMI-A with the ATM/ATR pathway, leading to the modulation of cell cycle regulating proteins, that can break the metastases cell cycle progression off.
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Genistein potentiates the anti-cancer effects of gemcitabine in human osteosarcoma via the downregulation of Akt and nuclear factor-κB pathway
Chengzhen Liang, Hao Li, Chengchun Shen, Jianbo Lai, Zhongli Shi, Bing Liu and Hui-min Tao
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00072]

Genistein, a nontoxic flavonoid compound, has potent antitumor activity in various cancer cells. In the present study, we investigated whether genistein could be employed as a novel strategy to enhance the anti-tumor activity of gemcitabine using human osteosarcoma MNNG/HOS tumor model. In vitro, by MTT, electron microscopy, immunobloting and qRT-PCR assay, we found that the combination treatment of genistein and gemcitabine resulted in stronger growth inhibition and apoptosis induction through the down-regulation of NF-κB activity and Akt activation in osteosarcoma cells. Moreover, the synergetic effects were observed when genistein was replaced by PI3K/Akt-pathway inhibitor (LY-294002) or NF-κB inhibitor (BAY11-7082). In vivo, the combination therapy augmented tumor growth inhibition through the down-regulation of NF-κB activity and Akt activation in xenografts. Taken together, these results provide in vitro and in vivo evidence that genistein abrogates gemcitabine-induced activation of NF-κB and increases the chemosensitization of osteosarcoma to gemcitabine. Combination therapy appears as a rational and novel approach for osteosarcoma treatment.
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AnticancerActivity and Anti-inflammatory studies of 5-Aryl-1,4-benzodiazepine Derivatives
Cortez-Maya Sandra, Cortés Cortés Eduardo, Hernández-Ortega Simón, Ramírez Apan Teresa, Nieto Camacho Antonio, Irina V. Lijanova and Martínez-García Marcos
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00073]

A series of 5-aryl-1,4-benzodiazepines with chloro- or fluoro-substituents in the second ring have been synthesized and their anti-inflammatory, myeloperoxidase and anticancer properties studied. The synthesized compounds showed potential anti-inflammatory and anticancer activities, which were enhanced in the presence of a chloro-substituent in the second ring of the 5-aryl-1,4-benzodiazepine.
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Neutrophil Elastase as a Target in Lung Cancer
Gautier MOROY, Alain J.P. ALIX, Janos SAPI, William HORNEBECK and Erika BOURGUET
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00074]

Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary diseases, has been recently involved in non-small cell lung cancer progression. It can act at several levels (i) intracellularly, clearing for instance the adaptor molecule insulin receptor substrate-1 (IRS-1) (ii) at the cell surface, hydrolyzing receptors as CD40 (iii) in the extracellular space, generating elastin fragments i.e. morphoelastokines which potently stimulate cancer cell invasiveness and angiogenesis.

Since decades, researchers identified natural compounds and/or synthesized agents which antagonize HNE activity that will be described in this review article. Some of these compounds might be of value as therapeutic agent in lung cancer. However, it is now widely accepted that lung tumor invasion and metastasis involve proteolytic cascades. Accordingly we will here mainly focus our attention to natural substances able to display a dual inhibitory capacity (i.e. lipids and derivatives, phenolics) towards HNE and matrix metalloproteinases (MMPs), particularly MMP-2. To that purpose we recently synthesize substances named “LipoGalardin” (Moroy G. et al, Biochem. Pharmacol., 2011, 81(5),626-635) exhibiting such inhibitory bifunctionality. At last, we will propose an original synthetic scheme for designing a potent biheaded HNE/MMP-2 inhibitor.
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Effects of bioactive compounds from carrots (Daucus carota L.), polyacetylenes, beta-carotene and lutein on human lymphoid leukaemia cells
Rana G Zaini, Kirsten Brandt, Malcolm R Clench and Christine L Le Maitre
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00075]

New therapies for leukaemia are urgently needed. Carrots have been suggested as a potential treatment for leukaemia in traditional medicine and have previously been studied in other contexts as potential sources of anticancer agents. Indicating that carrots may contain bioactive compounds, which may show potential in leukaemia therapies. This study investigated the effects of five fractions from carrot juice extract (CJE) on human lymphoid leukaemia cell lines, together with five purified bioactive compounds found in Daucus carota L, including: three polyacetylenes (falcarinol, falcarindiol and falcarindiol-3-acetate) and two carotenoids (beta-carotene and lutein). Their effects on induction of apoptosis using Annexin V/PI and Caspase 3 activity assays analysed via flow cytometry and inhibition of cellular proliferation using Cell Titer Glo assay and cell cycle analysis were investigated. Treatment of all three lymphoid leukaemia cell lines with the fraction from carrot extracts which contained polyacetylenes and carotenoids was significantly more cytotoxic than the 4 other fractions. Treatments with purified polyacetylenes also induced apoptosis in a dose and time responsive manner. Moreover, falcarinol and falcarindiol-3-acetate isolated from Daucus carota L were more cytotoxic than falcarindiol. In contrast, the carotenoids showed no significant effect on either apoptosis or cell proliferation in any of the cells investigated. This suggests that polyacetylenes rather than beta-carotene or lutein are the bioactive components found in Daucus carota L and could be useful in the development of new leukemic therapies. Here, for the first time, the cytotoxic effects of polyacetylenes have been shown to be exerted via induction of apoptosis and arrest of cell cycle.
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The cytotoxic effect of emetine and CGP-74514A studied with the Hollow Fiber Model and ArrayScan Assay in neuroendocrine tumors In Vitro
Dhana E. Larsson, Saadia B. Hassan, Kjell Öberg and Dan Granberg
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00076]

Emetine and CGP-74514A has previously shown antitumor activity in neuroendocrine tumor cell lines. The aim of this study was to investigate the cytotoxic activity of the drugs in a three-dimensional model and to study if the mechanism of the cytotoxic activity was induction of apoptosis.
An in vitro hollow fiber model was used to study the cytotoxic effect and a multiparametric high-content screening assay was used for measurement of apoptosis. The human pancreatic carcinoid cell line, BON-1 and the human typical and atypical bronchial carcinoid cell lines NCI-H727 and NCI-H720 were tested. Emetine and CGP-74514A showed higher antitumor activity on NCI-H720 compared to NCI-H727 and 3 day cultures were more sensitive than the 14 day cultures. A time- and dose-dependent activation of caspase-3 and increase in nuclear fragmentation and condensation were observed for the drugs in NCI-H727 and BON-1 using a multiparametric apoptosis assay. These results were confirmed with nuclear morphological examinations on microscopic slides.

Emetine and CGP-74514A showed antitumor activity and induced caspase-3 activation with modest changes in nuclear morphology, indicating induction of apoptosis.
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Anticancer Effects of the Organosilicon Multidrug Resistance Modulator SILA 421
Ulrike Olszewski-Hamilton, Robert Zeillinger, Meltem Demirel Kars, Attila Zalatnai, Jozsef Molnar and Gerhard Hamilton
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00077]

1,3-dimethyl-1,3-bis(4-fluorophenyl)-1,3-bis{3-[1(4-butylpiperazinyl)]-propyl}-disiloxan-tetrahydrochlorid (SILA 421) is a compound that was developed as modulator of the ABC cassette transporter P-glycoprotein. Furthermore, it exerted antimicrobial toxicity, vascular effects, downregulation of chaperone induction and plasmid curing in bacterial cells. Here, this drug was found to possess cytotoxic activity against a panel of human cancer cell lines that do not overexpress P-gp, with 50% inhibitory concentrations ranging between 1.75±0.38 μM for GLC14 small cell lung cancer and 34.00±4.75 μM for PC-3 prostate cancer cells. HL-60 leukemia and MDA-MB-435 breast cancer cells exhibited cell cycle arrest and apoptotic cell death in response to SILA 421. Assessment of global gene expression of SILA 421-treated HL-60 cells was employed to identify cellular pathways affected by the compound and revealed disturbance of DNA replication, transcription and production of apparently misfolded proteins. Endoplasmatic reticulum stress and downregulation of cell cycle, repair mechanisms and growth factor circuits eventually resulted in induction of apoptosis in this cell line. Reversal of resistance to taxanes, which had been reported for SILA 421 and the related molecule SILA 409 may be linked to downregulation of gene expression of kinesins in addition to the well-established P-gp-inhibitory effect. Interference with DNA replication and transcription seem to be the common denominator of antimicrobial activity, plasmid curing and anticancer toxicity in human cell lines. Thus, in consideration of the full range of putative cellular targets found in the present work, the application of these SILA compounds for treatment of tumors should be further evaluated.
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Differential expressions of matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs and their endogenous inhibitors among histologic subtypes of lung cancers
Yasuhiro Hida and Jun-ichi Hamada
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00078]

Lung cancer is a heterogeneous disease with several histologic subtypes. The two major pathologies, which account for approximately 70% of lung cancers, are adenocarcinoma (AD) and squamous cell carcinoma (SQ). Traditionally, these two subtypes have been categorized as non-small-cell lung cancer and treated similarly. However, they are different not only pathologically, but also functionally. For example, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), which assesses glucose metabolism in tumor tissues, shows that SQ has higher glucose metabolism than does AD.

 Matrix metalloproteinases (MMPs) and their inhibitors play pleiotropic roles in cancer development, carcinogenesis, apoptosis, angiogenesis, invasion and metastasis. Expression of MMPs and their associated molecules is different among the subtypes of lung cancer. Expression levels of MMP-2, MMP-7, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), tissue inhibitors of metalloproteinase (TIMP)-1, and TIMP-2 are higher in AD than in SQ. In contrast, expression levels of MMP-1, MMP-8, MMP-9 and TIMP-3 are higher in SQ than in AD.
 Serum levels of a disintegrin and metalloproteinase (ADAM)-8 and ADAM-28 are higher in lung cancer patients than in healthy controls. High expression of ADAM-28 correlates with metastasis and recurrence, but there is no significant difference in ADAM-8 or ADAM-28 expression between AD and SQ.

 It is necessary to recognize the differential expression patterns of MMPs, their endogenous inhibitors and associated molecules for each subtype of lung cancer in order to develop clinical markers, therapeutic inhibitors and treatment strategies using MMP inhibitors.
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Triple-negative breast cancer and Poly(ADP-ribose) polymerase inhibitors
Youngjin Park, Ayako Moriyama, Tomoaki Kitahara, Yutaka Yoshida, Tasuku Urita and Ryoji Kato
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00079]

Recent gene profiling studies have identified at least 5 major subtypes of breast cancer, including normal type, luminal A type, luminal B type, human epidermal growth factor receptor (HER)-2 positive type, and basal-like type. Triple-negative breast cancer (TNBC), showing no or low expressions of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor (HER)-2 HER2, considered important clinical biomarkers, accounts for 10% to 20% of all breast cancers. Hormonal therapy and molecular targeted therapy are not indicated for the management of TNBC, resulting in poor outcomes. Because TNBC lacks clear-cut therapeutic targets, effective treatment strategies remain to be established. However, TNBC is known to share similar biologic characteristics with basal-like type breast cancer and is often accompanied by loss of functional BRCA, a gene-modifying enzyme. Breast cancer with BRCA1 or BRCA2 mutations is accompanied by activation of the enzyme poly(ADP-ribose) polymerase (PARP). PARP, a DNA base-excision repair enzyme, is known to play a central role in gene repair, along with BRCA. Because some breast cancers with BRCA1 or BRCA2 mutations are TNBC, the suppression of PARP has attracted attention as a new treatment strategy for TNBC. In this article, we review the clinical characteristics of TNBC, discuss problems in treatment, and briefly summarize the international development status of PARP inhibitors.
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Gallium phthalocyanine photosensitizers: carboxylation enhances the cellular uptake and improves the photodynamic therapy of cancers
Jin F. Zhao, Jing Wang, Ji-Yao. Chen, Wadzanai Chidawanykia, T, Nyokong, Kazuyuki Ishii, N and Kobayashi
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00080]

The octacarboxyl gallium (GaPcC) and metal-free (H₂PcC) phthalocyanines were prepared using the carboxyl as the peripheral substituent. The carboxylation improves the intracellular delivery of these two PcCs into KB and QGY cancer cells as compared to that of sulfonated aluminum phthalocyanines (AlPcS), a popularly used photosensitizer (PS). Moreover GaPcC maintains high photo-production of singlet oxygen. With a short incubation time of 3 hours, GaPcC accumulates sufficiently in both KB and QGY cells and improves photodynamic therapy (PDT) by effectively killing these cancer cells. AlPcS and H₂PcC show much lower PDT effects under the same conditions, because AlPcS have a slow cellular uptake rate resulting in a low cellular amount and the ability of H₂PcC to produce ¹O₂ is low. Carboxylation is a promising way to prepare water-soluble metal phthalocyanines (MPcCs) and facilitates the cellular uptake of MPcCs for PDT improvement.
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A new 4-phenyl-1,8-naphthyridine derivative affects carcinoma cell proliferation by impairing cell cycle progression and inducing apoptosis
A. Capozzi, E. Mantuano, P. Matarrese, G. Saccomanni, C. Manera, V. Mattei, L. Gambardella, W. Malorni, M. Sorice and R. Misasi
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00082]

 In targeted cancer therapy the search for novel molecules lead to the discovery of a plethora of small organic molecules inhibiting cancer cell proliferation. Among these, quinazoline and derivatives, such as quinolines and naphthyridines, have been considered as of particular interest. One of these, the naphthyridine derivative 4-phenyl-2,7-di(piperazin-1-yl)-1,8-naphthyridine, has been analyzed in detail in the present work. We found that this compound elicited a powerful anti-proliferative activity on carcinoma cells, with IC₅₀ values comparable with paradigmatic microtubule-deranging drugs. The mechanisms underlying this effect were seemingly due to a framework of cellular alterations that include peculiar alterations of mitochondria, i.e. an increase of mitochondrial membrane potential (MMP), followed by the typical MMP loss leading to the release of apoptogenic factors, and cell death by apoptosis. Furthermore,, the analysis of cell cycle revealed that a significant percentage of treated cells was in G2/M phase. This block was seemingly due to a target effect of the naphthyridine derivative on microtubular network dynamic instability, which impaired mitotic spindle formation, possibly leading to mitotic catastrophy. Since the dual effects of naphthyridine derivative on cell cycle and mitotic spindle were obtained at very low concentrations, i.e. micromolar concentrations, we hypothesize that this compound could represent a new promising tool in the control of cancer cell proliferation.
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The role of Cdc25A in the regulation of cell proliferation and apoptosis
Tao Shen and Shile Huang
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00083]

Cell division cycle 25 A (Cdc25A), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (CDKs), such as CDK2, CDK4, and CDK6, and positively regulates the activities of CDKs that lead to cell cycle progression. In addition, Cdc25A also acts as a regulator of apoptosis. Overexpression of Cdc25A promotes tumorigenesis, and is frequently observed in various types of cancer. Here we briefly summarize current understanding of the role of Cdc25A in cell proliferation and apoptosis, as well as the impact of overexpression of Cdc25A on tumorigenesis.
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Boronated Compounds for Imaging Guided BNCT Applications
Simonetta Geninatti-Crich, Annamaria Deagostino, Antonio Toppino, Diego Alberti, Paolo Venturello and Silvio Aime
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00084]

Boron neutron capture therapy (BNCT) is based on the capture of thermal neutrons by boron 10 (¹⁰B) nuclei that have been selectively delivered to tumor cells.The amount of 10-30 μg of boron for g of tumor mass is needed to attain an acceptable therapeutic advantage. Despite the potentialities of BNCT have been demonstrated in several preclinical studies, this technique has not yet been fully accepted in the armoury of tools for tumor treatment. This is partly due to the differences in the uptake and distribution of ¹⁰B among patients and also to the uncertainty found in the determination of tumor-to-blood ¹⁰B concentration ratio. Attention is now being payed to use the main imaging techniques to determine the in vivo biodistribution of BNCT agents. Most of the work has been devoted to the most promising BNCT agents, namely BPA, BSH and carborane derivatives. This review surveys studies carried out over the last decade, and outlines the role that NMR, PET and SPECT imaging may have to improve the efficacy of BNCT.
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Design of N-substituted aminobutyric hydroxamic acid histone deacetylase inhibitors reveal an essential role for cap atomic composition
Jean Michel Brunel, Chanaz Salmi-Smail, Audrey Restouin, Thomas Prébet, Norbert Vey and Yves Collette
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00085]

A series of N-substituted aminobutyric hydroxamic acid histone deacetylase inhibitors derivatives was designed in good-to-excellent yields and evaluated for their antiproliferative activity in a panel of human cancer cell lines, showing half maximum effective concentration varying from 700 nM to > 100 μM. Interestingly, the replacement of a furyl group by a thienyl one impacted very significantly the cap role on this antiproliferative activity and on histone acetylation induced by these drugs in cell-based but also in cell-free enzyme assays, suggesting an important role of the electronic density attached to the oxygen or sulfur atoms.
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Pro-apoptotic Activity of BH3-only Proteins and BH3 Mimetics: from Theory to Potential Cancer Therapy
Mariusz L. Hartman and Malgorzata Czyz
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00086]

The evasion of cancer cells from the induction of cell death pathways results in the resistance of tumor to current treatment modalities. Therefore, the resistance to cell death, one of the hallmarks of cancer, is a major target in the development of new approaches to selectively affect cancer cells. The complex interplay between individual members of Bcl-2 family regulates both cell survival and the mitochondrial pathway of apoptosis by maintaining mitochondrial membrane integrity (anti-apoptotic Bcl-2 subfamily) and by triggering its disruption in response to stress stimuli (Bax-like subfamily). BH3-only proteins, another Bcl-2 subfamily, act either by direct stimulation of pro-apoptotic proteins of the Bax subfamily or by interfering with anti-apoptotic proteins of the Bcl-2 subfamily. Thus, pro-apoptotic BH3 mimetics, thought to function as BH3-only proteins, are expected to improve the effectiveness of cancer treatment. BH3 mimetics could be either natural or synthetic, peptidic or only based on a helical peptide-like scaffold. Experimental and clinical evidence indicates that BH3 mimetics may not be sufficient to cure cancer patients when used as a single agent. BH3 profiling of cancer cells was introduced to better predict the in vivo responsiveness of tumor to BH3 mimetics combined with conventional therapies. In summary, targeting the Bcl-2 proteins is a promising tool with potential to generate new treatment modalities and to complement existing anti-cancer therapies. This review presents the current knowledge on BH3-only proteins and the spectrum of strategies employing BH3 mimetics in preclinical and clinical studies that aim at tumor targeting.
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Antiangiogenic drugs in the treatment of advanced epithelial ovarian cancer
Parham Khosravi-Shahi and Luis Cabezón-Gutiérrez
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00087]

Epithelial ovarian cancer (EOC) accounts for approximately 80-90% of all ovarian cancers, and 75% of the patients are diagnosed with advanced disease (stage III and IV). Front-line systemic chemotherapy improves survival in women with advanced EOC; however, tumor recurrence occurs in almost all advanced EOC patients at a median of 15 months from diagnosis, and 5-year survival is estimated at 10 to 30%. Additionally, around 20% of patients do not respond to standard front-line therapy.Tumoral angiogenesis plays an important role in the pathogenesis of EOC, and its inhibition might improve survival in patients with advanced EOC. High-grade EOC is characterized by overexpression of vascular endothelial growth factor (VEGF), which drives dysfunctional tumor-associated angiogenesis, contributing to high interstitial pressure and increased vascular permeability. Diverse anti-angiogenic drugs are under investigation, and direct targeting of this pathway can be achieved by sequestration of VEGF protein using monoclonal antibodies (bevacizumab) or engineered binding site molecules (aflibercept), blockade of the VEGF receptor-2 with monoclonal antibodies or inhibition of receptor associated tyrosine kinase with low molecular weight inhibitors (cediranib, pazopanib, sorafenib or BIBF-1120).
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A novel fusicoccin derivative preferentially targets hypoxic tumor cells and inhibits tumor growth in xenografts
Koshi Kawakami, Miho Hattori, Takatsugu Inoue, Yuriko Maruyama, Junko Ohkanda, Nobuo Kato, Miki Tongu, Takaya Yamada, Miho Akimoto, Keizo Takenaga, Takeshi Sassa, Junji Suzumiya and Yoshio Honma
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00088]

Malignant cells in solid tumors survive under prolonged hypoxia and can be a source of resistance to current cancer therapies.  Tumor hypoxia is also associated with a more malignant phenotype and poor survival in cancer patients. Recent progress in our understanding of the biology of tumor cells under hypoxia has led to increased attention on targeting hypoxia for cancer therapy.  We report here that a novel fusicoccin derivative (ISIR-042), but not its parent or related compounds such as fusicoccin A and cotylenin A, is more cytotoxic to hypoxic cells than to normoxic cells.  The hypoxia-induced accumulation of hypoxia-inducible factor (HIF)-1α and the phosphorylation of Akt were effectively inhibited by treatment with ISIR-042, suggesting that the preferential cytotoxicity toward hypoxic cells is associated with a reduction of HIF-1α and Akt activation.  ISIR-042 inhibited the growth of human pancreatic cancer MIAPaCa-2 cells while sparing normal endothelial cells, and significantly inhibited the growth of MIAPaCa-2 cells as xenografts without apparent adverse effects.  Pancreatic cancer cells expressing CD24 and CD44 exhibited characteristics of stem cells.  Treatment with gemcitabine increased this stem cell-enriched population, and this effect was significantly inhibited by ISIR-042, suggesting that ISIR-042 preferentially inhibits stem/progenitors in pancreatic cancer cell lines compared with chemotherapeutic agents.  These results suggest that ISIR-042 may be a potential therapeutic agent for hypoxic tumors such as pancreatic cancer.
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Modulation Of Mmps By Cell Surface Integrin Receptor α5β1
Sekhar Pal, Kirat Kumar Ganguly, Shuvojit Moulik and  Amitava Chatterjee
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00091]

MMPs are a family of Zn dependent endopeptidases, which can mediate degradation of ECM components during various physiological and pathological processes including cancer. Some ECM components, through interaction with integrin receptor and modulation of downstream signaling, are capable of regulating expression and activity of several MMPs. α₅β₁ integrin is the universally accepted receptor for the ECM component fibronectin (FN). The present review deals with the downstream signaling involved in the α₅β₁ integrin mediated modulation of expression and activity of MMPs and their effector responses in different cellular system.
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Inhibiting Matrix Metalloproteinases, An Old Story With New Potentials For Cancer Treatment
Dimitris Stellas and Evangelia Patsavoudi
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00092]

Five decades of extensive research have passed since the description for the first time of the existence of an enzyme, which had the ability to degrade collagen during the metamorphosis of tadpoles. In fact, during these years, a large family of enzymes possessing the unique ability of degrading the extra cellular matrix (ECM) has been discovered. These enzymes are widely known as Matrix Metalloproteinases (MMPs) and it is noteworthy that many members of this family are directly linked to several human diseases such as arthritis and cancer. Moreover, due to the critical role of certain members of MMPs in cancer invasion and metastasis, great efforts have been made in order to find new inhibitory compounds against these MMPs. In this work we attempt to summarize the current status of the intervention strategies against MMPs, using inhibitory compounds that could block the activation of MMPs directly or indirectly. Further more we will try to shed light towards new potential strategies of MMP inhibitors using monoclonal antibodies.
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Regulation Of Mmps During Melanoma Progression: From Genetic To Epigenetic
Antonicelli Frank, Vallerand David, Trussardi-Regnier Aurélie, Grange Florent, Hornebeck William and Bernard Philippe
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00093]

Melanoma is the most severe skin cancer characterized by a bad prognosis at metastatic stages due to resistance to most classical chemotherapies. Invasion of melanoma cells into the surrounding microenvironment locally and at distance of the primary tumour, is facilitated by expression of proteases that degrade the extracellular matrix. Matrix metalloproteinases (MMP) have been long thought as potential therapeutic targets as they are involved in several steps of tumour progression. However, based on this general concept, broad spectrum MMP inhibitors showed weak anticancer potential. Furthermore, MMPs are also expressed by stroma and infiltrating cells. Although, inflammatory conditions lead to uncontrolled expression of MMPs leading to massive matrix destruction, these enzymes are also essential for immune cells to migrate towards the tumour site, and hence mount an anti-tumoral response. During stromal reaction, MMPs also act as non-matrix deteriorating enzymes, and thus modulating the inflammatory response through limited proteolysis of cytokines and chemokines. MMPs contribution to these processes depends on their activity and their expression. Besides the classic control level of transcription by a variety of growth factors and cytokines, the contribution of epigenetic mechanisms on MMPs expression was demonstrated of great importance to extend our knowledge about the role of these enzymes in a specific context such as melanoma progression. Understanding MMPs regulation by epigenetic drugs in melanoma and infiltrated cells will provide a new platform to develop efficient therapies. The therapeutic implication of epigenetic mechanisms to switch a pro-tumoral inflammatory towards an immune anti-tumoral response will be an exciting challenge in which MMPs expression could play a major role.
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Micrornas In Cancer: Small Molecules, Big Chances
Mohammed Abba, Giridhar Mudduluru and Heike Allgayer
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00094]

MicroRNAs have come to represent a significant mechanism of post transcriptional gene regulation affecting processes as varied as cellular differentiation, proliferation, metabolism, apoptosis, and cancer. As more miRNAs are unravelled and their roles dissected, it has become evident that the involvement of these molecules in cancer is much more extensive than initially thought.  Several miRNA expression analyses in both haematological malignancies and solid tumors have shown that, aside significant differences in expression between tumor and normal states, distinct tumor specific miRNA signatures exist. Additionally, the ability of miRNAs to mediate both oncogenic and tumor suppressor functions further broadens their functional significance. In recent years, efforts have intensified to utilize miRNAs therapeutically, especially in the context of oncomirs. As far as the impact and the success of this approach are concerned, it is still early days, but the potential is enormous. This review focuses on the important miRNAs that have been found to impact the tumorigenic process, how far we have come in terms of utilizing these molecules for therapy and the outlook for the near future.
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Novel Strategies for Hepatocellular Carcinoma Based on MMPs Science
Isao Okazaki and Yutaka Inagaki
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00095]

Hepatocellular carcinoma (HCC) is a cancer with extremely poor prognosis. This review discusses the pathological characteristicsofmulti-step hepatocarcinogenesis, tumor growth, invasion and metastasis, the expression of matrix metalloproteinases (MMPs) and their inhibitorsvia signal transductionin relationto dedifferentiation of hepatoma cells. It introduces the reports on anti-cancer agents in the field of MMP science, and finally describes novel strategies for the early stages of HCCin relationto cancer stem cells.
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Introduction: MMPs, ADAMs/ADAMTSs Research Products To Achieve Big Dream
Isao Okazaki and Kazuki Nabeshima
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00096]

Matrix metalloproteinases (MMPs) areknown to participate in cancer invasion and metastasis. Copious research on MMPs and their inhibitors has promoted the understanding ofthe mechanisms of cancer invasion and metastasis as well as the development of effective drugs for cancer treatment. This review discusses the classification of MMPs andtissue inhibitors of metalloproteinases (TIMPs)in relationto tumor growth and invasion mechanisms via signal transduction, followed by the possibilities for cancer treatment. The review focuses especially on the development of anti-cancer agents in the field of MMP science.
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MMPs in Ovarian Cancer as Therapeutic Targets
Amer Karam and Oliver Dorigo
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00097]

In the United States, about 22,000 women will be diagnosed with ovarian cancer in 2011, and an estimated 14,000 patients will succumb to the disease [1]. Surgery and chemotherapy present the main treatment modalities, but despite the development of novel therapies, the overall 5 years survival for ovarian cancer patients with advanced disease at diagnosis remains at only about 30%. Novel therapeutic strategies are needed to prolong survival and achieve greater cure rates.

Matrix metalloproteinases (MMPs) are frequently expressed in ovarian cancer, and play an important role in the metastatic process.  MMPs mediate degradation of the basement membrane as a crucial step in epithelial transformation, ovarian tumorigenesis and intraperitoneal metastasis [2].  Various preclinical and clinical studies have demonstrated that MMPs might provide a suitable therapeutic target. This review summarizes important observations regarding the expression of MMPs in ovarian cancer, their biological role, and data from clinical trials targeting MMPs in ovarian cancer patients.
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RECKing MMP: Relevance of Reversion-inducing Cysteine-rich Protein with Kazal Motifs as a Prognostic Marker and Therapeutic Target for Cancer (A Review)
Siddavaram Nagini
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00098]

Reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) is a membrane-anchored glycoprotein that negatively regulates the activities of matrix metalloproteinases (MMPs) and inhibits tumor invasion, metastasis, and angiogenesis. RECK is essential for normal development and is a key mediator of tissue remodeling and stabilization of tissue architechture. Downregulation of RECK documented in a wide range of malignant neoplasms correlates with poor prognosis, and tumor metastasis. The RECK gene is a common negative target for oncogenic signals that act on the Sp1-binding site of the RECK promoter. Both natural and synthetic agents have been identified as upregulators of RECK. Several strategies have been proposed to enhance RECK expression including forced expression of RECK, use of mimetics, recombinant peptides, microRNA antagonists, and gene therapy. Upregulation of RECK could be a valuable therapeutic option to improve prognosis and block tumor progression. This review addresses the potential value of RECK as a prognostic marker and as a molecular target for cancer therapy.
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Differential Expressions Of Matrix Metalloproteinases, A Disintegrin And Metalloproteinases, And A Disintegrin And Metalloproteinases With Thrombospondin Motifs And Their Endogenous Inhibitors Among Histologic Subtypes Of Lung Cancers
Yasuhiro Hida and Jun-ichi Hamada
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00099]

Lung cancer is a heterogeneous disease with several histologic subtypes. The two major pathologies, which account for approximately 70% of lung cancers, are adenocarcinoma (AD) and squamous cell carcinoma (SQ). Traditionally, these two subtypes have been categorized as non-small-cell lung cancer and treated similarly. However, they are different not only pathologically, but also functionally. For example, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), which assesses glucose metabolism in tumor tissues, shows that SQ has higher glucose metabolism than does AD. Matrix metalloproteinases (MMPs) and their inhibitors play pleiotropic roles in cancer development, carcinogenesis, apoptosis, angiogenesis, invasion and metastasis. Expression of MMPs and their associated molecules is different among the subtypes of lung cancer. Expression levels of MMP-2, MMP-7, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), tissue inhibitors of metalloproteinase (TIMP)-1, and TIMP-2 are higher in AD than in SQ. In contrast, expression levels of MMP-1, MMP-8, MMP-9 and TIMP-3 are higher in SQ than in AD.Serum levels of a disintegrin and metalloproteinase (ADAM)-8 and ADAM-28 are higher in lung cancer patients than in healthy controls. High expression of ADAM-28 correlates with metastasis and recurrence, but there is no significant difference in ADAM-8 or ADAM-28 expression between AD and SQ.

It is necessary to recognize the differential expression patterns of MMPs, their endogenous inhibitors and associated molecules for each subtype of lung cancer in order to develop clinical markers, therapeutic inhibitors and treatment strategies using MMP inhibitors.
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Chelating Systems for ^99mTc/¹⁸⁸Re in the development of Radiolabeled Peptide Pharmaceuticals
Cristina Bolzati, Davide Carta, Nicola Salvarese and Fiorenzo Refosco
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00102]

Currently, receptor based radiopharmaceuticals have received great attention in molecular imaging and radiotherapy of cancer, and provide a unique tool for target-specific delivery of radionuclides to pathological tissues. In this context, receptor binding peptides represent an attractive class of target vectors for Nuclear Medicine purposes. The rich chemistry of the group 7 elements elaborated in past years, has allowed the development of different procedures for the preparation of radiolabeled peptides in high yield. This, joint to the use of solid-phase peptide synthesis, has opened the possibility to explore new strategies for approaching the design of new class of radiolabeled receptor-targeted peptides, and to create new versatilities in targeting vehicle design e.g. in synthesis of metal-cyclized peptides or of multivalent targeting agents.

This review provides an overview on several aspects of the development of new ^99mTc/¹⁸⁸Re-peptide based target specific radiopharmaceuticals, in particular on the synthetic strategies employed for modifying molecular vectors, and the application of the different metal-cores and/or building block for preparing high specific activity agents.
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Peptide Receptor Radionuclide Therapy With Somatostatin Analogues In Neuroendocrine Tumors
Giampiero Giovacchini, Guillaume Nicolas and Flavio Forrer
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00103]

Neuroendocrine tumors (NETs) are rare tumors with variable malignant behavior. The majority of NETs express increased levels of somatostatin (SST) receptors, particularly SST₂ receptors. Radiolabeled peptides specific for the SST2 receptors may be used for diagnosis of NETs and for peptide receptor radionuclide therapy (PRRT). [¹¹¹In-DTPA⁰]-octreotide has been the first peptide used for PRRT. This radiolabeled peptide, emitting Auger electrons, often induced symptomatic relief, but objective morphological responses were rarely documented. After the introduction of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) other peptides, primarily [DOTA(0),Tyr(3)]octreotate (DOTATATE) and [DOTA(0),Tyr(3)]octreotide (DOTATOC) were labeled with ⁹⁰Y or ¹⁷⁷Lu and used for therapy applications. The rate of objective response obtained with these radiolabeled peptides ranges between 6% and 46%, owing to differences in inclusion criteria adopted in different studies, length and type of therapy, and criteria of evaluation of the response. The present data in the literature do not allow defining the most suitable peptide and radionuclide for the treatment of NETs. Instead emerging evidence indicates that a combination of nuclides with different physical characteristics might be more effective than the use of a single nuclide. Kidney and bone marrow toxicity are the limiting factors for PRRT. Mild toxicity is often encountered while severe toxicity is rarer. Toxicity could be reduced and therapeutic efficacy enhanced by patient-specific dosimetry. Future directions include different issues of PRRT, such as defining the most suitable treatment scheme, evaluation of new peptides with different affinity profiles to other SST receptor subtypes, and reduction of toxicity.
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Optical and Multimodal Peptide-Based Probes For In Vivo Molecular Imaging
Laura Melendez-Alafort, Pier Carlo Muzzio and Antonio Rosato
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00104]

Molecular imaging consists of non-invasive monitoring of spatial-temporal distribution of molecular or cellular processes, and may be used for early disease detection and real-time monitoring of therapeutic responses. Several strategies have been developed over the last two decades. Early attempts used monoclonal antibodies or antibody fragments and, although specific targeting was achieved, these probes was largely unsuccessful. In the quest for better agents, labeled peptides were then used. Peptides are easier to synthesize, less likely to be immunogenic, and have rapid blood clearance, which results in adequate target-to-background ratios in a short period of time.

This review discusses state-of-the-art cancer imaging by means of labeled peptides, the radionuclide, optical and nanoplatform-based imaging techniques which can provide functional information of the disease and track biochemical processes in vivo. The advantages and disadvantages of each technique are discussed. Lastly, the emphasis of this paper is on the new multimodal probes which can overcome individual limitations and exploit the individual strengths of the latest molecular imaging techniques.
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Drug Targeting Strategies for Photodynamic Therapy
Frédéric Schmitt and Lucienne Juillerat-Jeanneret
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00105]

In human pathologies, therapeutic treatments are often limited by the lack of selectivity of drugs and their elevated effective concentrations. Targeting these agents to a defined tissue could enhance their selectivity and then diminish their side effects when compared to drugs that accumulate in the entire body. Targeting could also improve treatment efficiency by allowing a localized high concentration of the agents. Based on the different behaviors and patterns of expression between diseased and normal cells, strategies for targeting can be explored. For example, receptors, proteases or trans-membrane carriers could be different or differently expressed. Many therapeutic procedures rely on this fact, including photodynamic therapy (PDT). PDT is already used in the treatment of some cancers, of inflammatory diseases and others diseases such as age-related macular degeneration or acne. PDT relies on the activation of a photosensitizer (PS) by visible light which results in the production of cytotoxic reactive oxygen species. In PDT, the general distribution of PS to the whole body leads to generalized photosensitization and poor acceptance of treatments by patients. One way to avoid these effects is to improve the targeting of PSs to diseased tissues using modification of PS with peptides or proteins that will target specific receptors or enzymes. PSs could also be functionalized with non-proteic ligands such as organometalics to achieve targeted and/or combined therapies. Alternatively, PSs could be encapsulated in nanoparticles bearing targeting agents which will decrease concentration of free circulating PS and improve photodynamic efficiency. These different approaches will be discussed in the present review with an emphasis on the use of peptides and proteins.
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Peptide-Receptor Ligands And Multivalent Approach
Paolo Ruzza, Anna Marchiani, Nicola Antolini and Andrea Calderan
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00106]

The overexpression of peptide receptors in human tumours makes peptide-ligands attractive agents for the development of specific diagnostic imaging and/or therapy of cancers. Solid-phase peptide synthesis, modern phage display technology and combinatorial peptide chemistry have profoundly affected the pool of available targeting peptides for efficient and specific delivery of imaging or therapeutic label molecules. Additionally, the availability of a wide range of bifunctional chelating agents for the radiolabelling of bioactive peptides with radionuclides has produced a wide variety of useful radiopharmaceutical molecules. This review article examines the principal receptors-binding peptides and their overexpression on tumour cells. We discuss the advantage and the challenges in developing multivalent peptide-based ligands summarizing their design strategies and applications.
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Molecular Imaging of Cancer with Radiolabeled Peptides and PET
Amy L. Vāvere and Raffaella Rossin
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00107]

Radiolabeled peptides hold promise for diagnosis and therapy of cancer as well as for early monitoring of therapy outcomes, patient stratification, etc.  This manuscript focuses on the development of peptides labeled with ¹⁸F, ⁶⁴Cu, ⁶⁸Ga and other positron-emitting radionuclides for PET imaging. The major techniques for radionuclide incorporation are briefly discussed. Then, examples of positron-emitting peptides targeting somatostatin receptors, integrins, gastrin-releasing peptide receptors, vasointestinal peptide receptors, melanocortin 1 receptors and others are reviewed.
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Flavonoids In Cancer Prevention
Eun-Jung Park and John M. Pezzuto
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00108]

Flavonoids are widely distributed in nature and a prevalent component of the human diet. Numerous biological activities have been reported. Some clinical trials or meta-analyses have suggested positive associations between flavonoid intake and human health, whereas others have not supported such a relationship. We currently highlight some responses that may be relevant to cancer chemoprevention, including antioxidation, anti-inflammation, and effects on NK cells. In addition, the prooxidant capacity of flavonoids may be relevant for the treatment of cancer. As is the case with other phytochemical constituents found in the diet, many questions over-shadow the results obtained with in vitro studies that do not take into account the ramifications of poor bioavailability, rapid and extensive metabolism, and physiologically relevant concentrations. To overcome some of these difficulties, greater emphasis has been placed on the study of methoxylated flavonoids, which may demonstrate more favorable pharmacokinetic properties. In terms of drug development, newer approaches such as nanotechnology could be useful. It is clear that flavonoids or flavonoid derivatives offer value for the chemoprevention of cancer. Many avenues of development are available and necessary for exploiting the impact on human health.
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Regulation of Cell Death And Survival By Resveratrol: Implications For Cancer Therapy
Simone Fulda
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00109]

Tissue homeostasis is maintained by tight control of signaling events that regulate cell death and cell survival. In addition, the antitumor activity of most cancer therapies, including chemotherapy, radiotherapy or immunotherapy, is mediated by the activation of apoptosis in cancer cells.

Apoptosis (programmed cell death) is a key regulatory mechanism that is critical to monitor tissue homeostasis during development as well as various organs of the adult organism. Accordingly, too little apoptosis can contribute to the pathogenesis of many human diseases, including cancer. Natural compounds, e.g. polyphenols such as resveratrol, have emerged as promising agents for cancer chemoprevention and therapy, since they interfere with various major signaling cascades that are aberrantly regulated in cancers. For example, resveratrol can antagonize signal transduction pathways that prevent apoptosis or support cancer cell proliferation. Further elucation of the molecular signaling events that are regulated by resveratrol is anticipated to path the way for the transfer of resveratrol and its derivatives into clinical application for chemoprevention or treatment of human cancer.
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Targeting Tumor Ubiquitin-Proteasome Pathway with Polyphenols for Chemosensitization
Min Shen, Tak Hang Chan and Q. Ping Dou
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00110]

The development of tumor drug resistance is one of the biggest obstacles on the way to achieve a favorable outcome of chemotherapy. Among various strategies that have been explored to overcome drug resistance, the combination of current chemotherapy with plant polyphenols as a chemosensitizer has emerged as a promising one. Plant polyphenols are a group of phytochemicals characterized by the presence of more than one phenolic group. Mechanistic studies suggest that polyphenols have multiple intracellular targets, one of which is the proteasome complex. The proteasome is a proteolytic enzyme complex responsible for intracellular protein degradation and has been shown to play an important role in tumor growth and the development of drug resistance. Therefore, proteasome inhibition by plant polyphenols could be one of the mechanisms contributing to their chemosensitizing effect. Plant polyphenols that have been identified to possess proteasome-inhibitory activity include (-)-epigallocatechins-3-gallate (EGCG), genistein, luteolin, apigenin, chrysin, quercetin, curcumin and tannic acid. These polyphenols have exhibited an appreciable effect on overcoming resistance to various chemotherapeutic drugs as well as multidrug resistance in a broad spectrum of tumors ranging from carcinoma and sarcoma to hematological malignances. The in vitro and in vivo studies on polyphenols with proteasome-inhibitory activity have built a solid foundation to support the idea that they could serve as a chemosensitizer for the treatment of cancer. In-depth mechanistic studies and identification of optimal regimen are needed in order to eventually translate this laboratory concept into clinical trials to actually benefit current chemotherapy.
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Natural-derived Polyphenols as Potential Anticancer Agents
Carmela Spatafora and Corrado Tringali
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00111]

In this short review we report selected examples from recent literature to show the potential of natural-derived, low molecular weight polyphenols as antitumor agents. The two major groups of polyphenol analogues have been reviewed here, namely flavonoids and stilbenoids. Notwithstanding these limitations, we listed 75 compounds, many of them representing only the most potent member in a library. In addition, many studies afforded useful SARs which may be the basis for future optimization. In this regard, it is worth highlighting the close structural relationships connecting some families of tubulin inhibitors, namely analogues of chalcones, combretastatin A-4, and resveratrol. Some interesting hybrid molecules have already been obtained, such as chalcone-combretastatin and chalcone-resveratrol hybrids. The optimization of natural polyphenols reputed to be anticarcinogenic has also been addressed to improve their metabolic stability and a number of  analogues, which are more stable to metabolic conversion and display comparable or higher antitumor activity than the parent compound, have been obtained. In some cases analogues with higher lipophilicity showed higher activity than the parent compound, in particular stilbenoids, flavanols, and flavone derivatives. Table 1 summarizes the main biological data on the natural-derived polyphenols cited within this review.

As a whole, this survey of recently reported, natural-derived polyphenols, though not exhaustive, clearly indicates that intensive research is being carried out in the area of antitumor polyphenol analogues and suggests that in the near future some polyphenolic leads may become useful anticancer drugs or adjuvants in cancer therapy.
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Structures Required Of Flavonoids For Inhibiting Digestive Enzymes
Hui Cao and Xiaoqing Chen
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00112]

The natural flavonoids as human digestive enzymes, such as α-glucosidase, α-amylase and aldose reductases inhibitors, have attracted great interest among researchers. The objective of this review is to overview the structures required of flavonoids for inhibiting these digestive enzymes. The hydroxylation on rings A and B of flavonoids improved the inhibition against these digestive enzymes. The hydroxylation on A-ring of flavones and isoflavones, especially at C-5 and C-7, significantly enhanced the inhibitory activities against digestive enzymes and the hydroxylation on positions C-3′ and C-4′ of B-ring of flavonoids remarkably improved the inhibition. The hydrogenation of the C2=C3 double bond on flavonoids decreased the inhibitory effects. The glycosylation of hyroxyl group on flavonoids weakened the inhibition against α-amylases and α-glucosidases. The glycosylation on 7-OH and 4'-OH of flavonoids significantly decreased the inhibition for aldose reductases. The glycosylation on 3-OH of flavonoids significantly increased or little affected the inhibition on aldose reductases. The methylation and methoxylation of flavonoids obviously weakened the inhibitory effects against α-amylase. The methylation and methoxylation of the hydroxyl group at C-3, C-3' and C-4' of flavonoids decreased or little affected the inhibitory potency against aldose reductases. And, the methylation and methoxylation of the hydroxyl groups at 5, 6, and 8 significantly increased the inhibitory capacity for aldose reductases. The methylation and methoxylation of flavonoids obviously affected the inhibitory effect for α-glucosidase in vitro depending on the replaced site.
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Probing the Interaction of Anti-cancer agent Dihydromyricetin with Human Serum Albumin: A typical method study
Tingting Chen, Shajun Zhu, Yapeng Lu, Yu Zhao, Guoqing Jiang, Li Zhu and Tianhong Lu
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00113]

The interaction between dihydromyricetin (DMY) with human serum albumin (HSA) under the physiological condition was investigated by fluorescence spectroscopy, circular dichroism (CD) spectra and UV-visible absorption spectroscopy. In the mechanism discussion it was proved that the fluorescence quenching of HSA by DMY is a result of the formation of DMY-HSA complex. Binding parameters calculated showed that DMY was bound to HSA with the binding affinities of 10⁵~10⁶ L·mol^-1. The enthalpy change (ΔH) and entropy change (ΔS) were calculated to be -28.76 kJ·mol^-1 and 18.21 J·mol^-1·K^-1, respectively, which implied that the hydrophobic and hydrogen bonds interactions play predominant roles in the binding process. The binding site of DMY on HSA may be located in hydrophobic cavity of subdomain IIA by the analysis data of fluorescence and synchronous fluorescence spectra. The specific binding distance r (3.37 nm) between donor (Trp-214) and acceptor (DMY) was obtained according to Förster non-radiative resonance energy transfer theory. CD spectral result demonstrates that DMY does not affect the secondary structure of HSA and can maintain protein stabilization. In addition, the effect of some common metal ions (e.g. Zn²⁺, Cu²⁺, Co²⁺, Ni²⁺, Fe³⁺) on the binding constant between DMY and HSA was examined.
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Immunomodulation And Anti-Inflammatory Roles Of Polyphenols As Anticancer Agents
François Ghiringhelli, Cédric Rébé, Aziz Hichami and Dominique Delmas
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00114]

Cancers are the largest cause of mortality and morbidity in industrialized countries. Several new concepts have emerged in relation to mechanisms that contribute to the regulation of carcinogenesis processes and associated inflammatory effects such as the modulation of innate immune cells and adaptive immune cells that could infiltrate the tumor. In the tumor microenvironment, there is a delicate balance between antitumor immunity and tumor-originated proinflammatory activity, which weaken antitumor immunity. Consequently; modulation of immune cells and inflammatory processes represent attractive targets for therapeutic intervention in malignant diseases with the goal to restore the sensitivity of cancer cells to chemotherapies and to overcome resistance to current cytotoxic therapies.
Numerous studies have reported interesting properties of dietary polyphenols in anticancer strategies notably by their pleiotropic properties on cancer cells, immune cells and inflammation.

This review is dedicated to the current knowledge of the mechanisms of polyphenols (resveratrol, curcumin, genistein and epigallocatechin) against cancers through a modulation of the immune system and the pro-inflammatory mediator production. We describe the effects of polyphenols on the adaptative and innate immune cells that could infiltrate the tumor. Reduction of chronic inflammation or its downstream consequences may represent a key mechanism in the fight of cancer development and polyphenols could reduce various pro-inflammatory substance productions through targeting signal transduction or through antioxidant effects. Lastly, we analyze key molecular links between inflammation and tumor progression through nuclear factors such as NFκB or microRNAs.
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Bovine Serum Albumin Significantly Improves The DPPH Free Radical Scavenging Potential Of Dietary Polyphenols And Gallic Acids
Hui Cao, Xiaoqing Chen and Koichiro Yamamoto
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00115]

The polyphenols-protein interaction is reversible in that the polyphenols-protein complex can dissociate and release the free polyphenols. The aim of this study is to evaluate the contribution of polyphenol-protein interactions (PPI) on improving the DPPH radical scavenging capacity of polyphenols. The DPPH radical scavenging potential of polyphenols was determined from 1 to 7 days under aerobic condition. The DPPH radical scavenging capacity of polyphenols depended on the structures of dietary polyphenols and gallic acids. The DPPH radical scavenging percentages of H-group polyphenols were weakened when kept in room temperature from 1 to 7 days. BSA rapid weakened the DPPH radical scavenging activity of polyphenols on the first day. However, the DPPH scavenging capacities of polyphenols in the presence of BSA overwhelmingly improved with increasing time. These results illustrated that BSA not only prolongs the effective time, but also improved the DPPH radical scavenging potential of polyphenols. The increasing DPPH scavenging percentages of polyphenols were slightly decreased with increased affinities of BSA-polyphenol complexes.
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A Small-Molecule Inhibitor, 5′-O-Tritylthymidine, Targets FAK And Mdm-2 Interaction, And Blocks Breast And Colon Tumorigenesis In Vivo
Vita Golubovskaya, Nadia L. Palma, Min Zheng, Baotran Ho, Andrew Magis, David Ostrov and William G. Cance
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00116]

Focal Adhesion Kinase (FAK) is is overexpressed in many types of tumors and plays an important role in survival. We developed a novel approach, targeting FAK-protein interactions by computer modeling and screening of NCI small molecule drug database. In this report we targeted FAK and Mdm-2 protein interaction to decrease tumor growth. By macromolecular modeling we found a model of FAK and Mdm-2 interaction and performed screening of >200,000 small molecule compounds from NCI database with drug-like characteristics, targeting the FAK-Mdm-2 interaction. We identified 5′-O-Tritylthymidine, called M13 compound that significantly decreased viability in different cancer cells. M13 was docked into the pocket of FAK and Mdm-2 interaction and was directly bound to the FAK-N terminal domain by ForteBio Octet assay. In addition, M13 compound affected FAK and Mdm-2 levels and decreased complex of FAK and Mdm-2 proteins in breast and colon cancer cells. M13 re-activated p53 activity inhibited by FAK with Mdm-2 promoter. M13 decreased viability, clonogenicity, increased detachment and apoptosis in a dose-dependent manner in BT474 breast and in HCT116 colon cancer cells in vitro. M13 decreased FAK, activated p53 and caspase-8 in both cell lines. In addition, M13 decreased breast and colon tumor growth in vivo. M13 activated p53 and decreased FAK in tumor samples consistent with decreased tumor growth. The data demonstrate a novel approach for targeting FAK and Mdm-2 protein interaction, provide a model of FAK and Mdm-2 interaction, identify M13 compound targeting this interaction and decreasing tumor growth that is critical for future targeted therapeutics.
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Mitoxantrone Targets The ATP-Binding Site Of FAK, Binds The FAK Kinase Domain And Decreases FAK, Pyk-2, C-Src, And IGF-1R, Pyk-2 In Vitro Kinase Activities
Vita Golubovskaya, Baotran Ho, Min Zheng, Andrew Magis, David Ostrov and William Cance
[Purchase Article] [BSP/ACAMC/E-Pub/00117]

Focal Adhesion Kinase (FAK) is a non-receptor kinase  that is overexpressed in many types of tumors and plays a key role in cell adhesion, spreading, motility, proliferation, invasion, angiogenesis, and survival.    Recently, FAK has been proposed as a target for cancer therapy, and we performed computer modeling and screening of the National Cancer Institute (NCI) small molecule compounds database to target the ATP-binding site of FAK, K454.   More than 140,000 small molecule compounds were docked into the crystal structure of the kinase domain of FAK in 100 different orientations using DOCK5.1 that identified small molecule compounds, targeting the K454 site, called A-compounds.  To find the therapeutic efficacy of these compounds, we examined the effect of twenty small molecule compounds on cell viability by MTT assays in  different cancer cell lines. One compound, A18 (1,4-bis(diethylamino)-5,8-dihydroxy anthraquinon) was a mitoxantrone derivative and significantly decreased viability in most of the cells comparable to the to the level of FAK kinase inhibitors TAE-226 (Novartis, Inc) and PF-573,228 (Pfizer).  The A18 compound specifically blocked autophosphorylation of FAK like TAE-226 and PF-228.  ForteBio Octet Binding assay demonstrated that mitoxantrone (1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino) ethylamino] anthracene-9,10-dione directly binds the FAK-kinase domain. In addition, mitoxantrone significantly decreased the viability of breast cancer cells in a dose-dependent manner and inhibited the kinase activity of FAK and Y56/577 FAK phosphorylation at 10-20 μM. Mitoxantrone did not affect phosphorylation of EGFR, but decreased Pyk-2, c-Src, and IGF-1R kinase activities. The data demonstrate that mitrotraxone decreases cancer viability, binds FAK-Kinase domain, inhibits its kinase activity, and also inhibits in vitro kinase activities of Pyk-2 and IGF-1R. Thus, this novel function of the mitoxantrone drug can be critical for future development of anti-cancer agents and FAK-targeted therapy research.
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Anticoagulant and Fibrinolytic Drugs Possible Agents In Treatment Of Lung Cancer?
Vladimir Bobek
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00118]

The effect of anticoagulant adjuvant anti-tumor therapy depends on the cancer type and stage and on the type of the used anticoagulant drug. A striking response rate was described in experiments involving human patients with lung cancer. The aim of this study is to review anticoagulant and fibrinolytic drugs as antitumor agents with focus on their clinical use. The first part of the review evaluates the results of clinical studies. The results of early clinical research are promising and observations suggest novel approaches to the experimental therapy of lung cancer. The second part of the review shortly describes the problem of thrombosis in patients with lung cancer (incidence of thromboembolic disease and its pathogenesis). The third part briefly describes the antimetastatic and antitumor attributes of anticoagulants and fibrinolytics.
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In Vitro Synergistic Interaction between DTA0100 and Radiation in Human Cancer Cell Lines
Elisa Bordón, Leticia G. León, Carla Ríos-Luci, Pedro C. Lara and José M. Padrón
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00119]

DTA0100 is a new catalytic inhibitor of the human DNA topoisomerase IIα that induces G₂/M phase cell cycle arrest in human solid tumor cells lines from various malignancies. In our study, we investigated the effectiveness of the combined treatment of ionizing radiation with DTA0100 on the survival of three representative human solid tumor cell lines: HeLa (cervix), WiDr (colon) and SW1573 (non-small cell lung cancer). The concomitant treatment of DTA0100 and irradiation showed a synergistic and antagonistic effect in the three cell lines tested. A synergistic cytotoxic effect of the combination of DTA0100 and radiation was confirmed by the median drug effect analysis method. It was found that in those protocols where the drug was administered after radiation the most synergistic effect was achieved. Our study constitutes the first in vitro evidence for synergistic effects between DTA0100 and radiation. This combination therapy might thus be expected to be more effective than either treatment alone in patients with cervical, colon and non-small cell lung cancer cells.
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Gambogic Acid Is A Novel Anti-Cancer Agent That Inhibits Cell Proliferation, Angiogenesis And Metastasis
Xu Wang and Wantao Chen
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00120]

Gambogic acid (GA) is a caged xanthone that is derived from Garcinia hanburyi and functions as a strong apoptotic inducer in many types of cancer cells. The distinct effectiveness of GA has led to its characterization as a novel anti-cancer agent. There is an increasing number of research studies focused on elucidating the molecular mechanisms of GA-induced anti-cancer effects, and several critical signaling pathways have been reported to be influenced by GA treatment. In this review, we summarize the multiple functional effects of GA administration in cancer cells including the induction of apoptosis, the inhibition of proliferation and the prevention of cancer metastasis and tumor angiogenesis.
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Fig latex (Ficus carica L. cultivar Dottato) in combination with UV irradiation decreases the viability of A375 melanoma cells in vitro
Giulio Menichini, Carmine Alfano, Eugenio Provenzano, Mariangela Marrelli, Giancarlo A. Statti, Francesco Somma, Francesco Menichini and Filomena Conforti
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00121]

Melanoma and nonmelanoma skin cancers are among the most prevalent cancers in the human population. In the present work latex of Ficus carica cultivar Dottato from Italy collected from fruits and leaves was examined to assess its free radical-scavenging activity with 1,1-diphenyl-2 picrylhydrazyl (DPPH) and its phototoxicity on A375 human melanoma cells. The latex obtained from the fruits of Ficus carica cv. Dottato showed the best antiradical activity with an IC₅₀ value of 0.05 mg/ml while the latex obtained from the leaves showed the best antiproliferative activity with an IC₅₀ value of 1.5 mg/ml on the human tumor cell line A375 (melanoma) after irradiation at a specific UVA dose (1.08 J/cm²). Control experiments with UVA light or drugs alone were carried out without significant cytotoxic effects. Polyphenolic content of the samples was also evaluated. This is the first study comparing F. carica latex of leaves and fruits. Plant derived natural products have long been and will continue to be an important source for anticancer drug development.
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Methylenedioxy- and Ethylenedioxy-Fused Indolocarbazoles. Potent Human Topoisomerase I Inhibitors and Antitumor Agents
David E. Zembower, Yongping Xie, Ali Koohang, Mary J. Kuffel, Matthew M. Ames, Yasheen Zhou, Rama Mishra, Aye Aye Mar, Michael T. Flavin and Ze-Qi Xu
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00122]

The indolo[2,3-α]carbazole alkaloids constitute an important class of natural products with interesting and diverse biological activities. A series of novel ring-fused indolocarbazoles were synthesized and evaluated for inhibition of topoisomerase I-mediated relaxation of supercoiled DNA and in vitro antitumor activity.  The derivatives bearing a methylenedioxy or an ethylenedioxy ring the fused onto the nonglycosylated indole (1a, 1b) demonstrated more potent anti-topoisomerase I activity. The isopropylenedioxy analogue 1c was approximately half as active as 1a, while the O-dimethoxy analogue 1d and the regioisomers 2a and 2b were essentially devoid of measurable activity, implying that the stacking with the intact DNA strand has been impeded by these compounds due to steric hindrance. The newly synthesized indolocarbazoles were screened against the NCI’s 60 tumor cell lines. The order of activity, based on the mean GI₅₀ values, is as follows: 1a > 2a ~ 1d > 1b > MCR-47 > 2b. Though in general the analogues that showed potent activity against topoisomerase I (1a, 1b) also showed potent in vitro inhibition of tumor cell growth, the antitumor activity of the anti-topoisomerase I inactive 1d and 2a were intriguing. COMPARE analyses confirmed that the topoisomerase I is the primary target for 1a and 1b; however, other target(s) or pathway(s) may also be involved, with PLD1 and MERTK suggested. Further investigation of these molecular targets against these indolocarbazoles is warranted.
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Doxorubicin-Loaded Nanoparticles: New Advances in Breast Cancer Therapy
J. Prados, C. Melguizo, R. Ortiz, C. Vélez, P.J. Alvarez, J.L. Arias, M.A. Ruíz, V. Gallardo and A. Aranega
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00123]

Doxorubicin, one of the most effective anticancer drugs currently known, is commonly used against breast cancer.  However, its clinical use is restricted by dose-dependent toxicity (myelosuppression and cardiotoxicity), the emergence of multidrug resistance and its low specificity against cancer cells. Nanotechnology is a promising alternative to overcome these limitations in cancer therapy as it has been shown to reduce the systemic side-effects and increase the therapeutic effectiveness of drugs.  Indeed, the numerous nanoparticle-based therapeutic systems developed in recent years have shown low toxicity, sustained drug release, molecular targeting, and additional therapeutic and imaging functions. Furthermore, the wide range of nanoparticle systems available may provide a solution to the different problems encountered during doxorubicin-based breast cancer treatment. Thus, a suitable nanoparticle system may transport active drugs to cancer cells using the pathophysiology of tumours, especially their enhanced permeability and retention effects, and the tumour microenvironment. In addition, active targeting strategies may allow doxorubicin to reach cancer cells using ligands or antibodies against selected tumour targets. Similarly, doxorubicin resistance may be overcome, or at least reduced, using nanoparticles that are not recognized by P-glycoprotein, one of the main mediators of multidrug resistance, thereby resulting in an increased intracellular concentration of drugs. This paper provides an overview of doxorubicin nanoplatform-based delivery systems and the principal advances obtained in breast cancer chemotherapy.
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Polyphenols counteract tumor cell chemoresistance conferred by multidrug resistance proteins
Krystyna Michalak and Olga Wesołowska
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00126]

One of the main reasons of cancer resistance to chemotherapeutic treatment is the presence of different ABC multidrug transporters in plasma membranes. The transporters extrude wide spectrum of anticancer agents out of cancer cells at the expense of energy derived from ATP-hydrolysis. Plant-origin polyphenolic compounds, mainly flavonoids and stilbenes or their synthetic derivatives, can modulate the main ABC transporters responsible for cancer drug resistance, including P-glycoprotein, MRP1 and BCRP. The recent studies on different resistant cancer cell lines enabled the discovery of a number of polyphenolic compounds able to reverse drug resistance in vitro and these compounds could be promising candidates for further clinical trials. The review summarizes the recent advances in the field of polyphenols interaction with ATP-binding cassette multidrug transporters. The mechanism of flavonoids interactions with the multidrug transporters and the structure-activity relationship are also discussed.
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Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets
Poyil Pratheeshkumar, Chakkenchath Sreekala, Zhuo Zhang, Amit Budhraja, Songze Ding, Young-Ok Son, Xin Wang, Andrew Hitron, Kim Hyun-Jung, , Lei Wang, Jeong-Chae Lee and Xianglin Shi
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00129]

Cancer is the second leading cause of death worldwide. There is greater need for more effective and less toxic therapeutic and preventive strategies. Natural products are becoming an important research area for novel and bioactive molecules for drug discovery. Phytochemicals and dietary compounds have been used for the treatment of cancer throughout history due to their safety, low toxicity, and general availability. Many active phytochemicals are in human clinical trials. Studies have indicated that daily consumption of dietary phytochemicals have cancer protective effects against carcinogens. They can inhibit, delay, or reverse carcinogenesis by inducing detoxifying and antioxidant enzymes systems, regulating inflammatory and proliferative signaling pathways, and inducing cell cycle arrest and apoptosis. Epidemiological studies have also revealed that high dietary intakes of fruits and vegetables reduce the risk of cancer. This review discusses potential natural cancer preventive compounds, their molecular targets, and their mechanisms of actions.
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Chemoprevention of Breast Cancer By Dietary Compounds
Aditi Shirish Vadodkar, Suman Suman, Rajkumar Lakshmanaswamy and Chendil Damodaran
[Abstract] [FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00130]

Breast cancer is the leading cause of cancer-related deaths in women in the United States and many other countries. There is an immediate need for more effective and less toxic therapeutic and preventive strategies for many cancers, but especially for breast cancer. Natural products are being tested with a hope of identifying novel potent molecules as anticancer agents. Phytochemicals and dietary compounds have been used for the treatment of various illnesses throughout history due to their safety, low toxicity, and general availability. Currently, many active phytochemicals are in clinical trials. Preclinical and clinical studies have indicated that daily consumption of dietary phytochemicals reduces the risk of several cancers. Phytochemicals can inhibit, delay, or reverse carcinogenesis by inducing detoxifying and antioxidant enzymes, by regulating inflammatory/proliferative signaling pathways, and by inducing apoptosis. This review article describes some of the potential natural cancer preventive compounds, along with a mechanistic discussion of their interactions with key cellular signal transduction pathways as well as their contribution to the suppression of breast cancer cell growth.
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Unifying Mechanisms of Action of the Anticancer Activities of Triterpenoids and Synthetic Analogs
Stephen H. Safe, Paul L. Prather, Lisa K. Brents, Gayathri Chadalapaka and Indira Jutooru
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00131]

Triterpenoids such as betulinic acid (BA) and synthetic analogs of oleanolic acid [2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)] and glycyrrhetinic acid [2-cyano-3,11-dioxo-18β-oleana-1,12-dien-30-oc acid (CDODA)] are potent anticancer agents that exhibit antiproliferative, antiangiogenic, anti-inflammatory and pro-apoptotic activities.  Although their effects on multiple pathways have been reported, unifying mechanisms of action have not been reported.  Studies in this laboratory have now demonstrated that several triterpenoids including BA and some derivatives, celastrol, methyl ursolatee, β-boswellic acid derivatives, and the synthetic analogs CDDO, CDODA and their esters decreased expression of specificity protein (Sp) transcription factors and several pro-oncogenic Sp-regulated genes in multiple cancer cell lines.  The mechanisms of this response are both compound- and cell context-dependent and include activation of both proteasome-dependent and -independent pathways.  Triterpenoid-mediated induction of reactive oxygen species (ROS) has now been characterized as an important proteasome-independent pathway for downregulation of Sp transcription factors.  ROS decreases expression of microRNA-27a (miR-27a) and miR-20a/miR-17-5p and this results in the induction of the transcriptional “Sp-repressors” ZBTB10 and ZBTB4, respectively, which in turn downregulate Sp and Sp-regulated genes.  Triterpenoids also activate or deactive nuclear receptors and G-protein coupled receptors, and these pathways contribute to their antitumorigenic activity and may also play a role in targeting Sp1, Sp3 and Sp4 which are highly overexpressed in multiple cancers and appear to be important for maintaining the cancer phenotype.
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Anti-cancer and Other Bioactivities of Korean Angelica gigas Nakai (AGN) and Its Major Pyranocoumarin Compounds
Jinhui Zhang, Li Li, Cheng Jiang, Chengguo Xing, Sung-Hoon Kim and Junxuan Lü
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00132]

Korean Angelica gigas Nakai (AGN) is a major medicinal herb used in Asian countries such as Korea and China.   Traditionally, its dried root has been used to treat anemia, pain, infection and articular rheumatism in Korea, most often through boiling in water to prepare the dosage forms. The pyranocoumarin compound decursin and its isomer decursinol angelate (DA) are the major chemical components in the alcoholic extracts of the root of AGN.  The in vitro anti-tumor activities of decursin and/or DA against prostate cancer, lung cancer, breast cancer, colon cancer, bladder cancer, sarcoma, myeloma and leukemia have been increasingly reported in the past decade whereas the in vivo efficacy in mouse models was established only for a few organ sites.  Preliminary pharmacokinetics study by us and others in rodent models indicated that decursinol (DOH), which has much less in vitro direct anti-cancer activities by itself, is the major and rapid in vivo hydrolysis metabolite of both decursin and DA.  Besides decursin, DA and DOH, other chemical components in AGN such as polysaccharides and polyacetylenes have been reported to exert anti-cancer and anti-inflammation activities as well. We systematically reviewed the published literature on the anti-cancer and other bio-activities effects of AGN extract and decursin, DA and DOH, as well as other chemicals identified from AGN.  Although a number of areas are identified that merit further investigation, one critical need is first-in-human studies of the pharmacokinetics of decursin/DA to determine whether humans differ from rodents in absorption and metabolism of these compounds.
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The Cancer Preventive Effects of Edible Mushrooms
Tongtong Xu, Robert B. Beelman and Joshua D. Lambert
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00133]

An increasing body of scientific literature suggests that dietary components may exert cancer preventive effects. Tea, soy, cruciferous vegetables and other foods have been investigated for their cancer preventive potential. Some non-edible mushrooms like Reishi (Ganoderma lucidum) have a history use, both alone and in conjunction with standard therapies, for the treatment of various diseases including cancer in some cultures. They have shown efficacy in a number of scientific studies. By comparison, the potential cancer preventive effects of edible mushrooms have been less well-studied. With similar content of putative effective anticancer compounds such as polysaccharides, proteoglycans, steroids, etc., one might predict that edible mushrooms would also demonstrate anticancer and cancer preventive activity.   In this review, available data for five commonly-consumed edible mushrooms: button mushrooms (Agaricus bisporus), A. blazei, oyster mushrooms (Pleurotus ostreatus), shiitake mushrooms (Lentinus edodes), and maitake (Grifola frondosa) mushrooms is discussed. The results of animal model and human intervention studies, as well as supporting in vitro mechanistic studies are critically evaluated. Weaknesses in the current data and topics for future work are highlighted.
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Bioavailability and Pharmacokinetics of Genistein: Mechanistic Studies on its ADME
Zhen Yang, Kaustubh Kulkarni, Wei Zhu and Ming Hu
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00134]

Genistein, one of the most active natural flavonoids, exerts various biological effects including chemoprevention, antioxidation, antiproliferation and anticancer. More than 30 clinical trials of genistein with various disease indications have been conducted to evaluate its clinical efficacy. Based on many animals and human pharmacokinetic studies, it is well known that the most challenge issue for developing genistein as a chemoprevention agent is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large interindividual variations in clinical trials. In order to better correlate pharmacokinetic to pharmacodynamics results in animals and clinical studies, an in-depth understanding of pharmacokinetic behavior of genistein and its ADME properties are needed. Numerous in vitro/in vivo ADME studies had been conducted to reveal the main factors contributing to the low oral bioavailability of genistein. Therefore, this review focuses on summarizing the most recent progress on mechanistic studies of genistein ADME and provides a systemic view of these processes to explain genistein pharmacokinetic behaviors in vivo. The better understanding of genistein ADME property may lead to development of proper strategy to improve genistein oral bioavailability via mechanism-based approaches.
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Plants against Cancer: A Review on Natural Phytochemicals in Preventing and Treating Cancers and Their Drug ability
Hu Wang, Tin Oo Khor, Limin Shu, Zhengyuen Su, Francisco Fuentes and Jong-Hun Lee
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00135]

Cancer remains to be one of the leading causes of death in the United States and around the world. The advent of modern drug-targeted therapies has undeniably improved cancer patients' cares. However, advanced metastasized cancer remains untreatable. Hence, continued searching for a safer and more effective chemoprevention and treatment is clearly needed for the improvement of the efficiency and to lower the treatment cost for cancer care. Cancer chemoprevention with natural phytochemical compounds is an emerging strategy to prevent, impede, delay, or cure cancer.  This review summarizes the latest research in cancer chemoprevention and treatment using the bioactive components from natural plants. Relevant molecular mechanisms involved in the pharmacological effects of these phytochemicals are discussed. Pharmaceutical developmental challenges and opportunities in bringing the phytochemicals into the market are also explored. The authors wish to expand this research area not only for their scientific soundness, but also for their potential drug ability.
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Developing Phytoestrogens for Breast Cancer Prevention
Mandy M. Liu, Ying Huang and Jeffrey Wang
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00136]

Breast cancer is one of the most common types of cancer in women, and is the second leading cause of cancer-related deaths in the United States. Chemoprevention using phytoestrogens (PEs) for breast cancer may be a valid strategy. PEs are phytochemicals with estrogen-like structures and can be classified into four types: isoflavones, lignans, stilbenes and coumestans. They are widely distributed in diet and herbs and have shown anti-cancer activity via mechanisms including estrogen receptor modulation, aromatase inhibition, and anti-angiogenesis. Genistein, daidzein and resveratrol are some of the most studied PE examples. Quality control in product manufacturing and clinical study design is a critical issue in developing them as clinically effective chemopreventive agents for breast cancer.
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Prevention of Colitis-associated Cancer: Natural Compounds that target the IL-6 Soluble Receptor
Cate Moriasi, Dharmalingam Subramaniam, Shanjana Awasthi, Satish Ramalingam and Shrikant Anant
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00137]

The risk of developing colorectal cancer increases in patients with inflammatory bowel disease (IBD) and a growing body of evidence shows the critical role of interleukin (IL-6) in this process. IL-6 is both a pro- and anti-inflammatory cytokine whose effects are mediated through activation of STAT3. Recent studies have also demonstrated that IL-6 trans-signaling through its soluble receptor occurs in IBD and cancer. IL-6 trans-signaling therefore is emerging as an attractive approach to diminish the inflammatory signals in conditions of chronic inflammation. The purpose of cancer chemoprevention is to either delay the onset or progression from precancerous lesions. Natural compounds because of their low toxicity render themselves excellent candidates that can be administered over the lifetime of an individual.   With the focus of managing IBD over a long time and preventing onset of colitis-associated cancer, we believe that there should be increased research focus on identifying chemopreventive compounds that can render themselves to long term use possibly for the lifetime of predisposed individuals. Here, we review the role of IL-6 signaling in IBD and colitis-associated cancer and underscore the importance of searching for natural compounds that would target the IL-6 trans-signaling pathway as a way to diminish chronic inflammatory conditions in the gastrointestinal tract and possibly hamper the progression to colon cancer. We propose that effective screening and identification of natural chemopreventive compounds that target IL-6 trans-signaling has important implications for the development of optimal strategies against cancer development triggered by inflammation.
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The Nuclear Orphan Receptors Nr4a As Therapeutic Target In Cancer Therapy
Alexander J. A. Deutsch, Hannes Angerer, Tamara E. Fuchs and Peter Neumeister
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00138]

NR4A1 (Nur77), NR4A2 (Nurr1) and NR4A3 (Nor-1) are three members of the orphan nuclear receptor (NR) family referred to as NR4A family. This subgroup activates gene expression in a constitutive ligand-independent manner. These nuclear receptors are classified as early response genes that are induced by a diverse range of signals. These orphan NRs have been implicated in cell cycle regulation, apoptosis, inflammation, metabolism and more recently in carcinogenesis. The ultimate growth of a tumor depends not only on the rate of tumor cell proliferation, but also the rate of apoptosis and NR4A1 controls both, survival and death of cancer cells. It has been demonstrated that NR4A1 activities are regulated through its subcellular localisation. In the nucleus, NR4A1 can function in a context dependent manner either as an oncogenic survival factor, promoting cancer cell growth or as the opposite through the activation of apoptosis. Additionally, in an atypical fashion, it is a potent killer when migrating to the mitochondria, where it binds to Bcl-2 and converts its survival phenotype, triggering cytochrome c release and apoptosis. The most convincing evidence that nuclear orphan receptors function as critical tumor suppressors is the observation that the NR4A1 and NR4A3 double knock out mouse develops rapidly acute myeloid leukemia. Down regulation of NR4A1 and NR4A3 was a common feature in leukemic blasts from human AML patients. In particular, the recent identification of pro-apoptotic agents inducing NR4A expression or acting as agonists suggests that these members could serve as potential targets for cancer therapy.
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Calculation of Molecular Features with Apparent Impact on Both Activity Of Mutagens And Activity Of Anticancer Agents
Andrey A. Toropov, Alla P. Toropova, Emilio Benfenati, Giusippina Gini, Danuta Leszczynska and Jerzy Leszczynski
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00139]

The analysis of influence of molecular features which can be extracted from the simplified molecular input line entry system (SMILES) and involved in the process of the building up of a series of QSAR models (with different splits into training and test sets) by means of the CORAL software for mutagenicity and anticancer activity has been performed. The presence of nitrogen (sp³) is favorable for decrease of the both endpoints; the presence of only one cycle is also promotor for decrease of the both endpoints; and the presence of two or three cycles is favorable for increase of mutagenicity and decrease of anticancer activity. These findings provide useful criteria for further experimental and computational studies in the search for new anticancer agents.
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Anti-Metastatic and Anti-Angiogenic Properties Of Potential New Anti-Cancer Drugs Based on Metal Complexes Of Selenosemicarbazones
Manja Zec, Tatjana Srdic-Rajic, Aleksandra Konic-Ristic, Tamara Todorovic, Katarina Andjelkovic, Ivana Filipovic-Ljeskovic and Sinisa Radulovic
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00140]

Our previous studies showed that zinc (II), cadmium (II) and nickel (II) complexes with 2-formylpyridine selenosemicarbazone induce apoptosis in cancer cells via activation of mitochondrial pathway. Herein, we reported their antimetastatic properties. Nickel (II), and zinc (II) complexes exhibited the strongest inhibitory potential towards MMP-2/9, while all investigated compounds significantly decreased proteolytic activity of MMP-2/9 in human breast cancer MDA-MB-361 cells. As shown by in vitro transmembrane assays, nickel (II) complex was the most effective in inhibiting invasion of MDA-MB-361 cells, while the cadmium (II) complex was the most active in inhibiting HeLa cells invasion. In malignant cells, the complexes inhibited intracellular accumulation of reactive oxygen species, known for its pro-angiogenic properties via VEGF signaling, but no reduction in total cellular amount of VEGF was found. Furthermore, tubulogenesis test showed anti-angiogenic effect of the complexes in treated endothelial cells. Data indicate multiple mechanisms of the complexes’ anti-angiogenic properties.  In addition, they could modulate metastatic phenotype of tumor cells. Nickel (II) complex with 2-formylpyridine selenosemicarbazone revealed to be the most potent.
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The Role of Peroxisome Proliferator-Activated Receptor-γ in Breast Cancer
Ioly Kotta-Loizou, Constantinos Giaginis and Stamatios Theocharis
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00141]

Peroxisome Proliferator-Activated Receptor-γ (PPARγ) is an extensively studied ligand-activated nuclear hormone receptor that functions as transcription factor and plays an important role in diverse biological processes, such as lipid metabolism and insulin sensitization. Recent studies have demonstrated that PPARγ is over-expressed in many tumor types, including breast cancer, suggesting a possible role in tumor development and/or progression and a putative prognostic value. Moreover, naturally-occurring and synthetic PPARγ agonists promote growth inhibition, apoptosis and differentiation of tumor cells. The present review summarizes the available information on PPARγ expression in breast tumors and the use of PPARγ ligands as anti-cancer agents for breast cancer treatment, both in vitro and in vivo. Considering the data so far, specific PPARγ agonists seem to exert beneficial effects against breast cancer and may therefore represent potential therapeutic agents.
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Dual Roles of Sulforaphane in Cancer Treatment
Tongzhen Xu, Dongmei Ren, Xuefei Sun and Guotao Yang
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00142]

Sulforaphane (SFN), one of naturally occurring isothiocyanates (ITCs), has huge cancer chemopreventive potential. It modulates cell death, cell cycle, angiogenesis, susceptibility to carcinogens, invasion and metastasis and possesses antioxidant activities. It functions as an inhibitor of phase 1 enzymes and also as an inducer of phase 2 detoxification enzymes through different ways. NF-E2-related factor-2(Nrf-2), as well as mitogen-activated protein kinase (MAPK), is regulated by SFN. Intriguingly, strong evidence has showed the dark side of Nrf-2: Stable upregulation of Nrf-2-mediated survival pathway would protect cancer cells from a subset of chemotherapeutic agents tested. This suggested that overexpression of Nrf-2 resulted in enhanced resistance of cancer cells to chemotherapeutic agents. Hence, future studies will focus on clarifying the exact time and dose of SFN to modulate the Nrf-2 signal pathway during chemotherapy and the efficacy of coadministration of Nrf-2 modulators during chemotherapy in order to make full use of the beneficial effect of this agent while eliminating the potential side effects.
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Colon Adenocarcinoma Multidrug Resistance Reverted by Euphorbia Diterpenes: Structure-Activity Relationships and Pharmacophore Modeling
Mariana Reis, Ricardo J. Ferreira, Julianna Serly, Noélia Duarte, Ana M. Madureira, Daniel J. V. A. Santos, Joséph Molnár and Maria-José U. Ferreira
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00143]

Multidrug resistance (MDR) is a limiting step on the success of cancer chemotherapy. The drug efflux mediated by P-gp (P-glycoprotein) is one of the best studied mechanisms of MDR. This paper focuses on the inhibitory P-gp efflux activity, pharmacophore modeling and structure-activity relationships studies of sixteen macrocyclic diterpenes and polycyclic derivatives obtained from Euphorbia species. The MDR human colon adenocarcinoma cells (COLO 320 MDR) overexpressing P-gp were used as the biological model to screen for P-gp dependent efflux inhibitors. Most of the compounds showed potential as MDR reversal agents. Combined analysis of two different statistic algorithms, K-means clustering and Principal Component Analysis discriminated two clusters and showed a strong correlation between log P and MDR reversal activity for compounds 1-5. The most effective compounds (1-4 and 11-12) were tested in combination with doxorubicin and all potentiated its activity lowering the ID50. Pharmacophore modeling allowed the definition of an aromatic moiety as an additional feature to a previous published P-gp pharmacophore, creating a new five-point pharmacophore with enhanced selectivity for the most active compounds of the present study. Docking results also show the importance of an aromatic moiety, positively identifying the most relevant residues that can be linked to an inhibitory activity increase.
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CCR5 as a potential target in cancer therapy: inhibition or stimulation?
Alicia González-Martín, Emilia Mira and Santos Mañes
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00144]

Extensive evidence implicates CCR5 and its ligands in the biology of tumors, although there is considerable controversy regarding the role of this chemokine receptor in cancer progression.  The discrepancies between the pro- and anti-tumor effects of CCR5 might derive from its expression by cell types with opposing functions in tumor progression and the context in which tumors originate.  We propose that CCR5 is necessary for optimal activation of the adaptive immune response to tumors, and for the success of certain immunotherapeutic strategies.  Since efficient activation of T cell responses has broad implications in the success of some chemo- and radiotherapy protocols, activation of CCR5, rather than its inhibition, might provide new therapeutic opportunities for cancer treatment.
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Targeted therapy for advanced urothelial cancer of the bladder: Where do we stand?
Zhaowei Zhu, Zhoujun Shen and Chen Xu
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00145]

The treatment of advanced urothelial cancer of the bladder has evolved substantially during recent years. Chemotherapy has been the mainstay of treatment and confers survival advantage. Despite such advances, the chemotherapy of bladder cancer is far from satisfactory due to severe side effects. Targeted therapy with novel drugs directed at specific molecular pathways opens promising new avenues to improve patient outcome. A systematic review examined the clinical data for novel targeted agents in 10 phase Ⅱ trials, with a focus on bevacizumab, aflibercept, sunitinib, sorafenib, gefitinib, lapatinib and trastuzumab. Besides, we present studies on other novel, promising targeted agents, including pazopanib, cetuximab and everolimus. Although bevacizumab and trastuzumab have shown promising results for patients with advanced bladder cancer, other targeted agents have not achieved the same clinical benefit in this disease as seen in other common epithelial cancers. Ultimately, combination targeted therapy, sequential therapy, adjuvant and neoadjuvant therapy may yield the best outcomes.
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Experimental and Theoretical Advances in Functional Understanding of Flavonoids as Anti-Tumor Agents
B. Venkata Babu, Naveen Kumar Konduru, Waro Nakanishi, Satoko Hayashi, Naseem Ahmed and Petar M. Mitrasinovic
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00146]

The potential of flavonoids to act as anti-tumor agents has been recognized but not fully understood because flavonoids are acting at several stages in cancer progression with distinct structure-function relationships. A whole family of structurally different flavonoids is herein described by reviewing some critical aspects of their pro-oxidant behavior in vitro/vivo and in cell systems by which they may work as antioxidants. Different classes of flavonoids (chalcones, flavones, isoflavones, flavanols, flavanones and anthocyanins) are synthetically mimicked using natural product structure-antioxidant activity relationships that are relevant for their enhanced function against cancer as well as severe inflammation conditions under which an increased oxidative stress is often implicated. In the context of the common mechanisms of flavonoid action, clinical data on benefits of flavonoids in fighting against cancer are discussed. A structural basis needed to improve antioxidant activity of these agents is elaborated in more detail.
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Platinum Compounds: A Hope for Future Cancer Chemotherapy
Imran Ali, Waseem A. Wani, Kishwar Saleem and Ashanul Haque
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00147]

The discovery of cis-platin and its second and third generation analogues created a hope in cancer chemotherapy. Cis-platin and its second generation analogue carboplatin have been used for the treatment of some cancers. The third generation analogues have superior anti-cancer profiles for curing a few cancers. Unfortunately, certain side effects such as renal impairment, neurotoxicity and ototoxicity etc. are associated with these drugs. But, combination therapy makes these analogues more effective with fewer side effects. In addition, the results of some ongoing clinical trials will make the safety profile clear in near future. The present article describes the current status of cis-platin and its analogues in cancer chemotherapy. The special emphasis has been made on cis-platin discovery, development of second (carboplatin, oxaliplatin, nedaplatin) and third (lobaplatin, heptalatin) generation analogues, comparison of their chemotherapies, mechanism of action, therapeutic status, recent developments and chronology. Moreover, attempts have been made to describe the future perspectives of these drugs in the cancer treatment.
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Treatment Directed To Signalling Molecules In Patients With Advanced Differentiated Thyroid Cancer
José Manuel Gómez Sáez
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00148]

Mutation detection in samples from thyroid cancer with the addition of BRAF mutation, and also the detection of RAS, RET/PTC, and PAX8/PPARγ mutations, may also contribute to cancer diagnosis. On the other hand, the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway) and PI3K/Akt (lipid kinase phoshoinositid-3-kinase signaling pathway) play an important role in transmission of cell signals. The genes, coding the signaling cascade proteins (RET, RAS, BRAF, PI3K, PTEN, AKT), are mutated or aberrantly expressed in thyroid cancer derived from follicular thyroid cell. Genetic and epigenetic alternations, concerning MAPK/ERK and PI3K/Akt signaling pathways, contribute to their activation and interaction in consequence of malignant follicular cell transformation. The understanding of this molecular mechanism provides access to novel molecular prognostic and therapeutic strategies for inhibiting oncogenic activity of signaling pathways. This ability to investigate tumour biology would allow the selection of different drugs. Nowadays the most relevant are treatment directed to tyrosine kinase receptors that bind for a wide variety of ligands and frequently are mutated and induce a constitutive activation such that a chimerical protein expression takes place in follicular cells in the domain of RET, as well as in other receptors. Many molecules as: motesanib, sorafenib, vandetanib, sunitinib, XL-184, imatinib, axitinib, pazopanib, lenvatinib, combretastatin, gefitinib, cetuximab, bortezomib, thiazoldonedione have been developed. Some of them also can act in receptors of vascular endothelial growth factor and epidermal growth factor receptors. Information obtained through cytological or biopsy samples permits the study of complex metabolic or genetic pathways, thus providing researchers with a high throughput tool for elucidating changes in the global expression patterns seen in tumour cells and allowing different therapeutic strategies in thyroid cancer considering the predominant altered pathways observed in these samples.
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Rational Drug Design For Identifying Novel Multi-target Inhibitors For Hepatocellular Carcinoma
Ahmed Temirak, Mona Abdulla and Mahmoud Elhefnawi
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00149]

Hepatocellular carcinoma (HCC) is one of the hard-treating and high mortality cancers for which novel therapies are very much in need. Sorafenib is the first medication that is now approved for the treatment of patients with advanced HCC [1]. Sorafenib is a multikinase inhibitor targeting the Raf serine/ threonine kinases and the VEGFR1-3, PDGFR-b, c-Kit, Flt3 and p38 tyrosine kinases.

Here, an Insilco approach was directed to identify novel multi-kinase inhibitors as potential candidate therapies for HCC. The Molecular Operating Environment (MOE) was used for docking studies, pharmacophore building and virtual screening of chemical molecules databases. The docking/scoring methods of MOE were validated by reproducing the docking interactions and poses of Sorafenib with smallest root mean square deviations. The three receptors for which multi-targeting compounds were screened for were: B-Raf, p38 and VEGFR-2 tyrosine kinases. After identifying the main binding sites of the target receptors, we started our studies by the docking of Sorafenib in comparison to tyrosine kinase inhibitors collected from the literature. A pharmacophore based on the SAR of Sorafenib was built using flexible alignment methods.

Next, pharmacophore based virtual screening on four chemical molecules databases; Open NCI Database, Zinc, Maybridge and drug bank was done resulting in 2928 hit compounds that were subsequently subjected to filtration according to their binding free energies, interactions exhibited with the receptors, Insilco ADME properties and Lipinski’s rule of five for molecule drugability. Finally 7 compounds were selected as they exhibited excellent binding interactions with the receptors in addition to their high safety profile that are recommended for further development.
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Metformin: A Rising Star to Fight the Mesenchymal Epithelial Transition In Oncology
Guislaine Barrière, Michel Tartary and Michel Rigaud
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00150]

Metformin is a biguanide derivative which is widely prescribed as an oral drug for diabetes mellitus type 2. This old molecule has recently received a new attention because of its therapeutic properties in oncology, that seem to be independent of its action on glycemia homeostasis. The reappraisal of its pharmacological effects was supported by delineation of signaling pathways and more recently clinical trials. Numerous epidemiological studies showed that diabetics have an increased risk of several types of cancer and cancer mortality. Complex relationship between cancer and type 2 diabetes is going to be unraveled and recent observations revealed a significant action of metformin, but not other anti-diabetic agents, on cancer cells. As metformin may act as an anticancer drug through inhibition of mTOR, it might have greater benefice than suggested by insulin lowering alone. This review summarizes major publications on the link between cancer and metformin underscoring new implications of this chemical drug in oncology field. New perspectives about utilization of this molecule in clinical oncological routine, are described, particularly for patients whithout distrurbance of glucose homeostasis. As the epithelial mesenchymal transition (EMT) seems implicated into invasive process and metastasis in cancer, and as metformin is able to inhibit EMT pathways, it is important to highlight cellular mechanisms of metformin.
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JAK2 Inhibitors for Myelofibrosis: Why Are They Effective in Patients With and Without JAK2V617F Mutation?
Fabio P S Santos and Srdan Verstovsek
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00151]

An activating mutation (V617F) in the pseudokinase domain of the Janus kinase (JAK)-2 tyrosine kinase has been described in 90% of patients with polycythemia vera (PV) and 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (MF). The discovery of JAK2V617F stirred the development of JAK2 inhibitors for treatment of patients with MF, ET and PV. Similar to other tyrosine kinase (TK) inhibitors in current use, JAK2 inhibitors target the adenosine triphosphate (ATP) binding site at the TK domain and not the pseudokinase domain, thus affecting both mutated and wild-type kinases. In fact, clinical trials of these compounds have demonstrated improvements in constitutional symptoms and splenomegaly in patients with both mutated and wild-type JAK2 MF. It is believed that these drugs may act not only through inhibition of neoplastic cell proliferation, but also by downregulating signaling through proinflammatory cytokine receptors. In this article, we review the current state of JAK2 inhibitors and discuss why these drugs could be a valuable addition to the treatment armamentarium for patients with and without the JAK2V617F mutation.
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Anti-Cancer Effects of Curcumin On Head And Neck Cancers
Wei Gao, Jimmy Yu-Wai Chan, William Ignance Wei and Thian-Sze Wong
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00152]

Head and neck cancer is the sixth large type of cancer in the world. The treatment regimens for head and neck cancer encompass surgery, radiotherapy and chemotherapy. However, all current treatment regimens for head and neck cancer have adverse effects. Therefore, continuing investigations have been undertaken to seek less toxic therapies to reduce treatment morbidity for head and neck cancer. Substantial evidence has demonstrated that curcumin inhibited proliferation, migration, invasion and metastasis and induced apoptosis via modulating multiple signaling pathways in head and neck cancer. Curcumin also suppressed the growth of xenograft derived from head and neck cancer in vivo in animal models. This review summarizes the evidence demonstrating potential use of curcumin as a single chemotherapeutic agent or in combination with other chemotherapeutic agents and radiation to minimize their toxicity in head and neck cancer. Although curcumin has been shown to be safe at doses of 8 g/d in both phase I and phase II clinical trials, its bioavailability is poor. Overcoming the poor bioavailability of curcumin in the near future would facilitate its clinical use.
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Cytoskeletal Alterations That Confer Resistance to Anti-Tubulin Chemotherapeutics
Arun Kanakkanthara, Paul H. Teesdale-Spittle and John H. Miller
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00153]

Drugs that target microtubules are a successful class of anti-cancer agents that have been in clinical use for over two decades. Acquired resistance to these drugs, however, remains a serious problem. Microtubule alterations, such as tubulin mutations and altered β-tubulin isotype expression, are prominent factors in development of resistance. Changes in actin and intermediate filament proteins can also mediate sensitivity to microtubule-targeting drugs. This review focuses on the mechanisms by which alterations in cytoskeletal proteins lead to drug resistance. This information will be helpful for improving the targeting of microtubule toxins.
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Anticancer Activity of New Haloalkyl Camptothecin Esters against Human Cancer Cell Lines and Human Tumor Xenografts Grown in Nude Mice
Zhisong Cao, John Mendoza, Anthony Kozielski, Xing Liu, Albert DeJesus, Yang Wang, Chang-Guo Zhan, Dana Vardeman and Beppino Giovanella
[FULL-TEXT INQUIRY] [BSP/ACAMC/E-Pub/00154]

All chemotherapeutic agents currently in use have a narrow window of therapeutic index of 1 to 1.2.  Camptothecin ester compounds are reported to have a wider therapeutic index when being used to treat human xenografts in nude mice.  As a continuous effort in searching for better chemotherapeutic agents for treating cancers, new haloalkyl camptothecin and 9-nitrocamptothecin ester derivatives 2a-b and 3a-d were prepared by respective acylation of camptothecin 1a and 9-nitrocamptothecin 1b with the corresponding acylating agents.  These new derivatives were tested in vitro against 8 human cancer cell lines using 7 different concentrations ranging from 5 to 300 nM and also in vivo against various types of human tumor xenografts grown in nude mice.  Most of these new compounds started showing inhibitory effects on the growth of 8 cancer cell lines at concentration of 80 nM and achieved greater than 70% inhibitions against these cell lines when the concentration increased to 300 nM.  Compound 2a and 3a showed good activity against human tumor xenografts in nude mice.   Compared to mother compound camptothecin, 3a was much less toxic in mice with a better therapeutic index, having the potential to be further developed as a safer treatment for cancers.
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