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Editorial: Target therapy in brain
tumours and metastases
M. Caraglia and R. Addeo
[BSP/CCDT/E-Pub/00072]
An Epigenetic Approach to Pancreatic Cancer Treatment:
the Prospective Role of Histone Deacetylase Inhibitors
Nicola Tinari, Michele De Tursi, Antonino Grassadonia,
Marinella Zilli, Liborio Stuppia, Stefano Iacobelli and
Clara Natoli
[Abstract] [Purchase Article] [BSP/CCDT/E-Pub/00073]
Editorial: Molecularly
targeted treatments for colorectal cancer: advances and limitations
[BSP/CCDT/E-Pub/00074]
Synthetic lethality-based therapeutics: perspectives
for applications in colorectal cancer
Debora Soncini, Irene Caffa, Franco Patrone,
Alberto Ballestrero and Alessio Nencioni
[Abstract] [Purchase Article] [BSP/CCDT/E-Pub/00075]
Role of angiogenesis inhibitors in colorectal cancer:
sensitive and insensitive tumors
Luca Bagnasco, Daniela Piras, Silvio Parodi, Inga Bauer,
Gabriele Zoppoli, Franco Patrone and Alberto Ballestrero
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00076]
A multi-scale approach to colorectal cancer: from
a biochemical-interaction signaling-network level, to multi-cellular
dynamics of malignant transformation. Interplay with mutations
and onco-protein inhibitor drugs
L. Tortolina, N. Castagnino, C. De Ambrosi, E.
Moran, F. Patrone, A. Ballestrero and S. Parodi
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00077]
Patient-tailored treatments with anti-EGFR monoclonal
antibodies in advanced colorectal cancer: KRAS and beyond.
A. Ballestrero, A. Garuti, G.Cirmena, I. Rocco, C. Palermo,
A. Nencioni, S. Scabini, G. Zoppoli, S. Parodi and
F. Patrone
[Abstract] [Purchase Article] [BSP/CCDT/E-Pub/00078]
DNA damage response pathways and cell cycle checkpoints
in colorectal cancer: current concepts and future perspectives
for targeted treatment
Stéphanie Solier, Yong-Wei Zhang, Alberto
Ballestrero, Yves Pommier and Gabriele Zoppoli
[Abstract] [Purchase
Article] [BSP/CCDT/E-Pub/00079]
Second-generation tyrosine kinase inhibitors as first-line
treatment strategy in newly diagnosed chronic phase chronic
myeloid leukemia patients
Massimo Breccia and Giuliana Alimena
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00080]
Genetic variants in genes involved in mechanisms of
chemoresistance to anticancer drugs
Marin JJG, Briz O, Monte MJ, Blazquez AG and
Macias RIR
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00081]
Two novel GPER agonists induce gene expression changes
and growth effects in cancer cells
Rosamaria Lappano, Camillo Rosano, Maria Francesca
Santolla, Marco Pupo, Ernestina Marianna De Francesco, Paola
De Marco, Marco Ponassi, Andrea Spallarossa, Angelo Ranise
and Marcello Maggiolini
[Abstract] [Purchase Article] [BSP/CCDT/E-Pub/00082]
Recent Findings Confirm LIM Domain Kinases as Emerging
Target Candidates for Cancer Therapy
F. Manetti
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00083]
New Strategies in the Chemotherapy of Leukemia: Eradicating
Cancer Stem Cells in Chronic Myeloid Leukemia
A. Stefanachi, F. Leonetti, O. Nicolotti, M. Catto, L.
Pisani, S. Cellamare, C. Altomare and A. Carotti
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00084]
Multifaceted Mechanisms for Cell Survival and Drug
Targetingin Chronic Myelogenous Leukemia
Junya Kuroda, Yuji Shimura, Mio Yamamoto-Sugitani, Nana
Sasaki and Masafumi Taniwaki
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00085]
Antitumor effects of interferon-alpha on cell growth
and metastasis in human nasopharyngeal carcinoma
Xiong Liu, Juan Lu, Ming-Liang He, Zhi Li, Bao Zhang,
Li-Hui Zhou, Qi Li, Gang Li, Lu Wang, Wen-Dong Tian, Ying
Peng and Xiang-Ping Li
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00086]
Editorial: Novel and emerging drugs
for leukemias
Tadeusz Robak
[BSP/CCDT/E-Pub/00087]
Novel And Emerging Drugs For Acute Myeloid Leukemia
Eytan M. Stein and Martin S. Tallman
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00088]
Emerging therapies in chronic myeloid leukemia
Joanna Gora-Tybor
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00089]
Novel and emerging drugs for rarer chronic lymphoid leukaemias
Estella Matutes
[Abstract] [Purchase Article] [BSP/CCDT/E-Pub/00090]
Novel and emerging drugs for acute lymphoblastic leukemia
Ewa Lech-Maranda and Wojciech Mlynarski
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00091]
Pioglitazone Prevents Smoking Carcinogen-Induced Lung Tumor Development In Mice
Ming-Yue Li, Angel WY Kong, Huiling Yuan, Lily T Ma, Michael K.Y. Hsin, Innes YP Wan, Malcolm J Underwood and George G Chen
[Abstract] [Purchase Article] [BSP/CCDT/E-Pub/00092]
Structural Comparison of the Interaction of Tubulin with Various Ligands Affecting Microtubule Dynamics
Emilia Stec-Martyna, Marco Ponassi, Mariangela Miele, Stefania Parodi, Lamberto Felli and Camillo Rosano
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00093]
Cyclooxygenase-2 (COX-2) Mediates Arsenite Inhibition of UVB-induced Cellular Apoptosis in Mouse Epidermal Cl41 cells
Zhenghong Zuo, Weiming Ouyang, Jingxia Li, Max Costa and Chuanshu Huang
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00094]
High Cxcr4 Expression Correlates With Sunitinib Poor Response In Metastatic Renal Cancer
D’Alterio Crescenzo, Portella Luigi, Ottaiano Alessandro, Rizzo Mimma, Carteni Giacomo, Pignata Sandro, Facchini Gaetano, Perdonà Sisto, Di Lorenzo Giuseppe, Autorino Riccardo, Franco Renato, La Mura Anna, Nappi Oscar, Castello Giuseppe and Scala Stefania
[Abstract] [Purchase Article] [BSP/CCDT/E-Pub/00095]
Growth Suppression and Mitotic Defect Induced by JNJ-7706621, an Inhibitor of Cyclin-Dependent Kinases and Aurora Kinases
Aya Matsuhashi, Takatoshi Ohno, Masashi Kimura, Akira Hara, Masanao Saio, Akihito Nagano, Gou Kawai, Mitsuru Saitou, Iori Takigami, Kazunari Yamada, Yukio Okano and Katsuji Shimizu
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00096]
Lycopene modulation of molecular targets affected by smoking exposure
Paola Palozza, Rossella Simone, Assunta Catalano, Marco Russo and Volker Böhm
[Abstract] [Purchase Article] [BSP/CCDT/E-Pub/00097]
Polysialyltransferase: a new target in metastatic cancer
Robert A. Falconer, Rachel J. Errington, Steven D. Shnyder, Paul J. Smith and Laurence H. Patterson
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00098]
Inhibition of Protein N-Myristoylation: A Therapeutic Protocol in Developing Anticancer Agents
U. Das, S. Kumar, J. R. Dimmock and R. K. Sharma
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00099]
Novel and emerging drugs for chronic lymphocytic leukemia
Susanne Isfort, Paula Cramer and Michael Hallek
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00100]
Acid ceramidase as a chemotherapeutic target to overcome resistance to the antitumoral effect of choline kinase α inhibition
Ana Ramírez de Molina, Ana de la Cueva, Rosario Machado-Pinilla, Vanessa Rodríguez-Fanjul, Teresa Gómez del Pulgar, Arancha Cebrián, Rosario Perona and Juan Carlos Lacal
[Abstract] [Purchase Article]
[BSP/CCDT/E-Pub/00101]
A molecular signature for oncogenic BRAF in human colon cancer cells is revealed by microarray analysis
Tobias Joyce, Eftychia Oikonomou, Vivian Kosmidou, Eleni Makrodouli, Ioannis Bantounas, Spiros Avlonitis, Georgios Zografos and Alexander Pintzas
[Abstract] [FULL-TEXT INQUIRY]
[BSP/CCDT/E-Pub/00102]
Polysialyltransferase: a new target in metastatic cancer
Robert A. Falconer, Rachel J. Errington, Steven D. Shnyder, Paul J. Smith and Laurence H. Patterson
[Abstract] [FULL-TEXT INQUIRY]
[BSP/CCDT/E-Pub/00103]
Emerging roles for modulation of microRNA signatures in cancer chemoprevention
Karthik Neelakandan, Pradeesh Babu and Sujit Nair
[Abstract] [FULL-TEXT INQUIRY]
[BSP/CCDT/E-Pub/00104]
The impact of proteomics in the understanding of the molecular basis of paclitaxel-resistance in ovarian tumors
Daniele Vergara, Andrea Tinelli, Anna Iannone and Michele Maffia
[Abstract] [FULL-TEXT INQUIRY]
[BSP/CCDT/E-Pub/00105]
Increased Expression of Matrix Metalloproteinases Mediates Thromboxane A2-Induced Invasion in Lung Cancer Cells
Xiuling Li and Hsin-Hsiung Tai
[Abstract] [FULL-TEXT INQUIRY]
[BSP/CCDT/E-Pub/00106]
Anti-tumor effect of AlkB homolog 3 knockdown in hormone-independent prostate cancer cells
Kazuhisa Koike, Yuko Ueda, Hiroaki Hase, Kaori Kitae, Yasuyuki Fusamae, Seiko Masai, Takaaki Inagaki, Yasuka Saigo, Shinji Hirasawa, Kazuhiro Nakajima, Ikumi Ohshio, Yasutake Makino, Noboru Konishi, Hiroshi Yamamoto and Kazutake Tsujikawa
[Abstract] [FULL-TEXT INQUIRY]
[BSP/CCDT/E-Pub/00107]
Abstracts
Editorial: Target therapy in brain tumours and metastases
M. Caraglia and R. Addeo
[BSP/CCDT/E-Pub/00072]
Malignant gliomas are the most common type of primary brain
tumors and prognosis of patients with these cancers remains
poor despite standard treatment with radiotherapy and temozolomide.
The structure and functioning of the Blood Brain Barrier (BBB)
in brain tumours is controversial and has significant implications
for designing new therapeutic strategies. Therefore, it is
crucial to develop a strategy to allow drug delivery across
the BBB. One way is to use direct delivery strategies with
liposomal formulations.
Molecular targeted therapy provide new effective treatment
options with minimal toxicity; however, the involvement and
the interaction of several signalling pathways determine difficulties
to detect prevalent targets that can be successfully addressed
by novel agents. Therefore, the development of targeted therapy
for gliomas has been particularly challenging. Multi-targeted
kinase inhibitors, novel monoclonal antibodies, and new vaccines
have been developed. Standard treatments and current development
of new therapies for malignant gliomas are reviewed, focusing
specifically on growth factors and their receptors, as well
as the downstream intracellular effector molecules. Although
the histological and molecular genetic variability exists
within malignant gliomas, there are alterations in specific
cellular signal transduction pathways or cellular functions
which are common in most gliomas. This finding has led to
trials of novel molecularly targeted therapeutic agents alone,
and in various combinations, for patients with malignant gliomas.
Brain metastases, which occur in approximately 20–40%
of individuals with systemic cancer, represent a significant
cause of morbidity and mortality and overwhelm all other types
of brain tumors in terms of incidence and public health impact.
Recent advances in the treatment of many malignancies have
frequently been due to the incorporation of molecularly targeted
agents into the treatment regimen. The role of target-based
agents in the treatment of brain metastases from breast cancer
is not still clear even if this tumour disease has largely
taken advantage from the wide-spread use of target-based agents
such as trastuzumab or lapatinib. We will also discuss the
results derived from the trials using EGF-R-targeted agents
and anti-VEGF bevacizumab in the treatment of brain metastases
from non small cell lung cancer (NSCLC). Given our growing
experience with the feasibility and safety of multimodal chemo-radiotherapy
in the treatment of brain metatstases, as well as the fact
that intracranial responses often track extracranial responses
in chemotherapy-naıve patients, we will also discuss
the disease-specific treatment for patients with brain
metastases derived from different primary tumour sites.
This special issue provides the current understanding of potential
new therapeutic targets and keeps in consideration the action
and the potential benefits of some promising target-based
agents for the treatment of either primary or metastatic brain
tumors.
[Back to top]
An Epigenetic Approach to Pancreatic Cancer Treatment:
the Prospective Role of Histone Deacetylase Inhibitors
Nicola Tinari, Michele De Tursi, Antonino Grassadonia,
Marinella Zilli, Liborio Stuppia, Stefano Iacobelli and
Clara Natoli
[Purchase
Article] [BSP/CCDT/E-Pub/00073]
Pancreatic ductal adenocarcinoma (PDAC) is quite resistant
to conventional treatments, and gemcitabine, the standard
chemotherapeutic agent, offers only a small benefit. Development
and progression of PDAC is a complex process involving dysregulation
of multiple signal transduction pathways arising from not
only genetic but also epigenetic alterations. This makes the
epigenetic approach to the treatment of PDAC of great interest.
Histone deacetylases, a family of enzymes that, by removal
of acetyl groups from a variety of histone and nonhistone
proteins, play an important role in the epigenetic regulation
of gene expression, are frequently dysregulated in PDAC. In
particular, overexpression of class I histone deacetylases
has been related to higher tumor grade, poor prognosis and
development of chemoresistance. Histone deacetylase inhibitors
(HDACIs), a novel class of agents endowed with pleiotropic
antitumor effects, appear promising either for their preferential
toxicity towards transformed as compared to normal cells and
their ability to synergistically enhance the anticancer activity
of radiotherapy and many chemotherapeutic agents. Many HDACIs
have been shown to increase the antiproliferative and proapoptotic
effects of gemcitabine, 5-fluorouracil and bortezomib, a new
proteasome inhibitor, in vitro and in vivo
PDAC xenograft models. MGCD0103, romidepsin, panobinostat,
vorinostat and valproic acid, are currently being tested in
association with radiotherapy or chemotherapy (gemcitabine,
fluoropyrimidines, proteasome inhibitors) in phase I-II clinical
trials in patients with locally advanced or metastatic PDAC.
[Back to top]
Editorial: Molecularly targeted treatments for colorectal
cancer: advances and limitations
[BSP/CCDT/E-Pub/00074]
In the perspective of cancer treatment taking into account
the modern advancements of molecular oncology, molecular systems
biology and medicinal chemistry, I would point out four basic
converging directions, whose synergic effect could dramatically
change our degree of success in cancer therapy: We should
know much more systematically the multiple somatic
hereditary alterations in individual cancers (mostly
DNA level alterations, but aberrant CpG methylations come
also to my mind). In addition, both base-level DNA alterations
and chromosome-level alterations are important. In a context
of high throughput DNA sequencing, precisely with the intent
of achieving a much more systematic knowledge of cancer mutations,
a pioneering work was the one of the Vogelstein’s group.
In a set of 35 advanced colon cancers 140 mutations were found
globally (with the caveat that a relatively low detection
sensitivity required a >
5 % mutation frequency); each individual cancer would bear
an average of at least 15 mutations [1,2]. Mutation frequency
decreases precipitously: in a given cancer there are very
few high frequency mutations (driver mutations), and a vast
majority of progressively rarer ones. Examining the data from
the high-throughput DNA sequencing studies of the Vogelstein’s
group, we have observed what seems to behave as a scale-free
distribution [3] of cancer mutation frequencies. The probability
P of a mutation with a given mutation frequency k seems
to follow the law: P(k) ~ k-γ,
where γ
≈ 3 (unpublished observation).
A mutation database construction based on a careful collection
of literature data, together with new findings from high-throughput
studies, is represented by the “Catalog of Somatic Mutations
in Cancer” (COSMIC)[4].
An additional important question is related to the hypothesis
of a possible presence of de novo mutations in metastases.
If new mutations in metastases are an infrequent event [5],
this could be an advantage from a therapeutic point of view.
This may indeed imply that we have to face a primary tumor
which is predisposed to high cell shedding, rather than being
involved with rare, high implantation efficiency, hyper-mutated
(and consequently pharmacologically unpredictable) metastatic
cells.
Our knowledge of pathways and signaling network regions
should increase steadily. It seems important to state the
obvious: we are basically dealing with very complex networks
of (bio)chemical interactions and reactions, where not only
the description/reconstruction of “Molecular Interaction
Maps” (mostly networks of protein-protein interactions),
not only concentrations and rates, are important, but also
essential are the ballet in space and time of our molecules
and the roles played by cell compartments [6]. The cell is
a dynamic entity and dynamic simulations of sub-regions of
the network will become more and more important in the cancer
field, especially considering that our simulation capabilities
can expand to include the behavior of altered/mutated, dominant/recessive,
onco-proteins, the effect of onco-protein inhibitor drugs
and even the effect of siRNAs on specific targets. These dynamic
simulations, associated with a more systematic knowledge of
mutations/alterations in individual cancers, could help dramatically
toward a more appropriate/mechanistically-conscious usage
of “biological” antineoplastic drugs [7].
Stem-cell pathways, colon crypts stem cells: apart from the
possible development of late sub-clones in a large tumor,
somatically inherited alterations of the above considered
pathways still exist essentially in most cancer cells of any
given tumor because the process of carcinogenesis is a multi-hit
event endowed with somatic inheritance. However, a stem cell
at the bottom of a colon crypt could have encountered one
or more stem-cell-specific early mutations, implying a defect
of maturation toward terminal differentiation. The implied
pathways are still not well defined, but they could offer,
in the future, new targets for medicinal chemistry [8].
Points 1 and 2 are prerequisites for the interdisciplinary
work of medicinal chemistry directed toward
new drug discovery. Onco-proteins frequently
affected by excess of function, mutated or over-expressed,
suggest to the field of medicinal chemistry that it is perhaps
worthwhile to find a selective inhibitor drug for those newly
discovered targets. The same strategy can be extended to a
network of pathways. Inhibitor drugs active at different pathway
levels of colorectal cancer will be discussed in the present
CCDT special issue. We will not discuss further the crucial
complex role of medicinal chemistry in finding new targeted
drugs, only because it is not within the focus of this special
issue. Associations among dominant-onco-protein
inhibitors: a natural consequence of 30 years of
progress in molecular oncology and 10 years of progress in
reconstruction of molecular signaling networks, is the following.
If the process of neoplastic transformation is a multi-hit
event, this implies that a multiplicity of signaling-network
pathways have to be altered in order to reach the new homeostasis
of a cancer cell. A cancer cell is often “addicted”
to the excess of function of a mutated onco-protein. The exquisite
sensitivity to Gleevec (and new related compounds) of chronic
myeloid leukemias bearing a BCR/Abl translocation is a well
known case in point [9]. Mutations tend to be mutually exclusive
along the same pathway, but complementary toward the achievement
of malignancy for different pathways [10]. Associations of
correctly targeted inhibitors of two or three altered different
pathways could have strong synergic effects. Here the concepts
of tumor-addiction, and synthetic lethality applied not to
metabolism but to pathways, could come into play.
Last but not least, we also do not have to forget that even
traditional chemotherapic agents, for instance DNA-damaging
agents, could be the target of a selective approach. In breast
or ovarian cancer cells defective for BRCA1 or BRCA2 function,
an increased sensitivity to cisplatin and related compounds
can be induced by the administration of a PARP1 inhibitor.
This is because PARP1 plays an important role in base-excision
repair, while BRCA1/2 is important in homologous recombination.
In the presence of both losses of function, cancer cells are
largely unable to repair DNA damage, cell death results as
a consequence of a phenomenon of synthetic lethality. Normal
cells still have at least one BRCA1/2 functional allele and
therefore they tend to be more cisplatin resistant [11]. A
specific synthetic lethal killing of RAD54B-deficient human
colorectal cancer cells by FEN1 silencing was recently reported
[12].
The review articles of this special CCDT issue discuss several
aspects mostly related to the above points 1, 2 and 4.
[Back to top]
Synthetic lethality-based therapeutics: perspectives
for applications in colorectal cancer
Debora Soncini, Irene Caffa, Franco Patrone,
Alberto Ballestrero and Alessio Nencioni
[Purchase Article] [BSP/CCDT/E-Pub/00075]
Over the past two decades, progresses in colorectal cancer
treatment have significantly improved patient survival and
quality of life. However, unresectable metastatic colorectal
cancer remains virtually incurable, making the search for
new effective therapeutics mandatory. An important limitation
to the development of new agents has been the difficulty to
exploit mutated tumor suppressors or “undruggable”
oncogenes as a target. Recently, evidence that mutations in
tumor suppressors, such as BRCA1/2, make cancer cells highly
susceptible to inhibitors of a compensatory DNA repair pathway
[poly-(ADP-ribose) polymerase 1 (PARP1)] has broadened
the range of possible therapeutic targets by extending it
to gene products that are in a “synthetic lethal”
relationship with oncogenes and tumor suppressors. Inhibition
of such targets blocks specific buffer-mechanisms that are
required for survival in the presence of defined oncogenic
mutations, but not in their absence. As a consequence, selective
elimination of mutation-bearing cells results. This approach
has led to identify compounds that are highly active in the
presence of different types of mutated tumor suppressors and
oncogenes, including DNA repair genes, RAS, and Myc. In addition,
ongoing studies promise to identify new mechanisms which,
when pharmacologically interfered with, will selectively eradicate
mutated cancer cells. Here, we revise and discuss these new
aspects of cancer biology and highlight their potential applications
in colorectal cancer treatment.
[Back to top]
Role of angiogenesis inhibitors in colorectal cancer:
sensitive and insensitive tumors
Luca Bagnasco, Daniela Piras, Silvio Parodi, Inga Bauer,
Gabriele Zoppoli, Franco Patrone and Alberto Ballestrero
[FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00076]
Angiogenesis is a key factor in the carcinogenesis process.
In oncological practice, angiogenesis inhibition, mainly through
the blockade of the VEGF family and its receptors, has been
robustly demonstrated to produce clinical benefits and, in
specific disease subsets such as colorectal cancer, to extend
the overall survival of treated patients. VEGF is a multifunctional
growth factor that mediates its functions through cognate
receptors on endothelial cells and it has been discovered
for its capability to induce macromolecule hyperpermeability
in veins and venules.
Several approaches have been taken to target angiogenesis
in cancer: drugs that target one or more soluble ligands of
the VEGF family, drugs that selectively inhibit one or more
receptors of the VEGF receptor family, and drugs that inhibit
VEGF receptor(s) among other, non VEGF-related targets. At
present, two compounds have shown significant clinical activity,
bevacizumab, Avastin®
and aflibercept, Zaltrap®,
and only one of these (bevacizumab) has so far been registered
for use in clinical practice.
In the present review, we explore and summarize the main features
of the angiogenetic process, concerning in particular a common
and potentially lethal disease as colorectal cancer. We overview
the molecular pathways that characterize angiogenesis, focusing
on VEGF family, the current applications and limitations of
its blockade in oncology, and the hypothetical future perspectives
of anti-angiogenic therapy.
[Back to top]
A multi-scale approach to colorectal cancer: from
a biochemical-interaction signaling-network level, to multi-cellular
dynamics of malignant transformation. Interplay with mutations
and onco-protein inhibitor drugs
L. Tortolina, N. Castagnino, C. De Ambrosi, E.
Moran, F. Patrone, A. Ballestrero and S. Parodi
[FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00077]
This review article is part of a special Current Cancer Drug
Targets issue devoted to colorectal cancer and molecularly
targeted treatments. In our paper we made an attempt to connect
more basic aspects with preclinical, pharmacological / therapeutic
and clinical aspects. Reconstruction of a Molecular Interaction
Map (MIM) comprising an important part of the G0 – G1
– S cell cycle transition, was a major component of
our review. Such a MIM serves also as a convenient / organized
database of a large set of important molecular events. The
frequency of mutated / altered signaling-proteins indicates
the importance of this signaling-network region. We have considered
problems at different scale levels. Our MIM works at a biochemical-interaction
level. We have also touched the multi-cellular dynamics of
normal and aberrant colon crypts. Until recently, dynamic
simulations at a biochemical or multi-cellular scale level
were considered as a sort of esoteric approach. We tried to
convince the reader, also on the basis of a rapidly growing
literature, mostly published in high quality journals, that
suspicion towards simulations should dissipate, as the limitations
and advantages of their application are better appreciated,
opening the door to their permanent adoption in everyday research.
What is really required is a more interdisciplinary mentality
and an interdisciplinary approach. The prize is a level of
understanding going beyond mere intuition.
[Back to top]
Patient-tailored treatments with anti-EGFR monoclonal
antibodies in advanced colorectal cancer: KRAS and beyond.
A. Ballestrero, A. Garuti, G.Cirmena, I. Rocco, C. Palermo,
A. Nencioni, S. Scabini, G. Zoppoli, S. Parodi and
F. Patrone
[Purchase Article] [BSP/CCDT/E-Pub/00078]
Personalized medicine emphasizes the practice of considering
individual patient characteristics as opposed to that centered
on standards derived from epidemiological studies which, by
definition, do not take into account the variability of individuals
within a given population.
When applied to oncology, personalized medicine is an even
more complex concept because it extends the variability beyond
the individual patient to the individual tumor. Indeed, the
great genotypic and phenotypic variability (both in primary
and metastatic sites of cancer) the development of targeted
therapies, and the growing availability of biological assays
complicate the scenario of personalized medicine in the oncological
field.
In this paper we review the results of anti-epidermal growth
factor receptor (EGFR) monoclonal antibody (mAb) therapy in
metastatic colorectal cancer (mCRC) in the context of tumor
biology, delineating the future prospects of patient-tailored
medicine in this area. In particular, we deal with EGFR
inhibition by Cetuximab, a chimeric mouse human IgG1 mAb,
and panitumumab, a fully human IgG2 mAb.
We discuss the clinical impact of anti-EGFR mAbs on wild-type
(WT) KRAS mCRC, also taking into account the feasibility of
novel multi-marker approaches to treatment decision-making,
aimed at increasing the predictive power of pre-therapy biomarkers.
Experimental topics and fields of ongoing research, such as
targeting microRNAs (miRNAs) with novel anticancer drugs and
epigenetics in CRC are also addressed.
[Back to top]
DNA damage response pathways and cell cycle checkpoints
in colorectal cancer: current concepts and future perspectives
for targeted treatment
Stéphanie Solier, Yong-Wei Zhang, Alberto
Ballestrero, Yves Pommier and Gabriele Zoppoli
[Purchase
Article] [BSP/CCDT/E-Pub/00079]
Second-generation tyrosine kinase inhibitors as first-line
treatment strategy in newly diagnosed chronic phase chronic
myeloid leukemia patients
Massimo Breccia and Giuliana Alimena
[FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00080]
Recent results of phase II trials which used dasatinib or
nilotinib as single agent, or phase III trials comparing second-generation
tyrosine kinase inhibitors to imatinib, showed greater potency
of these two inhibitors in newly diagnosed chronic myeloid
leukemia (CML) patients in chronic phase (CP). In the present
review we detail and summarize clinical results of both agents
as first-line therapeutic strategy, (but) and also discuss
on critical points emerged from the last follow-up of trials
comparing new generation tyrosine kinase inhibitors with imatinib.
In terms of safety, dasatinib and nilotinib have shown favorable
toxicity profile, with peculiar and distinct pattern of adverse
events. Based on these results, USA FDA approved both drugs
as first-line treatment in newly diagnosed CML: now several
therapeutic strategies are available to treat patients at
onset of disease. Longer follow-up is however needed to prove
the advantages of faster and deeper responses in terms of
disease progression compared to imatinib.
[Back to top]
Genetic variants in genes involved in mechanisms of
chemoresistance to anticancer drugs
Marin JJG, Briz O, Monte MJ, Blazquez AG and
Macias RIR
[FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00081]
Refractoriness to the pharmacological treatment of cancer
is dependent on the expression levels of genes involved in
mechanisms of chemoresistance and on the existence of genetic
variants that may affect their function. Thus, changes in
genes encoding solute carriers may account for considerable
inter-individual variability in drug uptake and the lack of
sensitivity to the substrates of these transporters. Moreover,
changes in proteins involved in drug export can affect their
subcellular localization and transport ability and hence may
also modify the bioavailability of antitumor agents. Regarding
pro-drug activation or drug inactivation, genetic variants
are responsible for changes in the activity of drug-metabolizing
enzymes, which affect drug clearance and may determine the
lack of response to anticancer chemotherapy. The presence
of genetic variants may also decrease the sensitivity to pharmacological
agents acting through molecular targets or signaling pathways.
Recent investigations suggest that changes in genes involved
in DNA repair may affect the response to platinum-based drugs.
Since most anticancer agents activate cell death pathways,
the evasion of apoptosis plays an important role in chemoresistance.
Several genetic variants affecting death-receptor pathways,
the mitochondrial pathway, downstream caspases and their natural
modulators, and the p53 pathway, whose elements are mutated
in more than half of tumors, and survival pathways, have been
reported. The present review summarizes the available data
regarding the role of genetic variants in the different mechanisms
of chemoresistance and discusses their potential impact in
clinical practice and in the development of tools to predict
and overcome chemoresistance.
[Back to top]
Two novel GPER agonists induce gene expression changes
and growth effects in cancer cells
Rosamaria Lappano, Camillo Rosano, Maria Francesca
Santolla, Marco Pupo, Ernestina Marianna De Francesco, Paola
De Marco, Marco Ponassi, Andrea Spallarossa, Angelo Ranise
and Marcello Maggiolini
[Purchase Article] [BSP/CCDT/E-Pub/00082]
Although the action of estrogens has been traditionally explained
by the binding to and transactivation of the nuclear estrogen
receptor (ER)α
and ERβ,
recently the G protein-coupled receptor GPR30/GPER has been
involved in the rapid estrogen signaling. We investigated
the ability of two original molecules, which were named GPER-L1
and GPER-L2, to bind to and activate the GPER transduction
pathway in cancer cells. Competition assays, docking simulations,
transfection experiments, real-time PCR, immunoblotting, gene
silencing technology and growth assays were performed to ascertain
the selective action of GPER-L1 and GPER-L2 in activating
the GPER-mediated signaling. Both compounds, which did not
show any ability to bind to and activate the classical ERs,
were able to bind to GPER and to trigger the rapid activation
of the GPER/EGFR/ERK transduction pathway which led to the
up-regulation of GPER-target genes. Notably, GPER-L1 and GPER-L2
induced the proliferation of SkBr3 breast and Ishikawa endometrial
cancer cells at nM concentrations through GPER, hence providing
further evidence on their capability to elicit relevant biological
responses mediated by GPER. The identification and characterization
of these novel compounds as selective GPER agonists represent
a valuable tool to further dissect the pharmacology of this
novel estrogen receptor and to better differentiate the specific
functions elicited by each estrogen receptor subtype in cancer
cells.
[Back to top]
Recent Findings Confirm LIM Domain Kinases as Emerging
Target Candidates for Cancer Therapy
F. Manetti
[FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00083]
The two members of the LIM domain kinase family (LIMK1 and
LIMK2) represent crucial keys in the signaling pathways that
modulate the structure and activity of actin cytoskeleton.
They maintain the optimal balance between phosphorylated and
unphosphorylated cofilin that in turn acts by severing filamentous
actin into globular actin and ensures actin turnover and cytoskeleton
regulation. Many macromolecular partners able to regulate
LIMK activity (positive and negative regulators) do exist.
roteins that enhance or reduce the nucleocytoplasmic shuttling
of LIMK by direct or indirect interaction are also known.
Among many LIMK activators, members of the Rho family of small
GTPases (i.e., Rho, Rac, and Cdc42) and their downstream effectors
(i.e., ROCK, PAK, MK2) are involved in the progression of
various human cancers toward invasive and metastatic stages.
As LIMK are centrally positioned in the pathways leading to
cytoskeleton dynamics and regulation, they could be considered
as valuable targets for actin regulation. Fine modulation
of LIMK activity could be a major challenge to inhibit tumor
cell invasion mediated by one or a combination of the upstream
signaling factors. As LIMK play a critical role in tumor cell
invasion, they may be candidate targets for developing novel
therapeutic agents toward tumor invasion and metastasis.
[Back to top]
New Strategies in the Chemotherapy of Leukemia: Eradicating
Cancer Stem Cells in Chronic Myeloid Leukemia
A. Stefanachi, F. Leonetti, O. Nicolotti, M. Catto, L.
Pisani, S. Cellamare, C. Altomare and A. Carotti
[FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00084]
Chronic myeloid leukemia (CML) is a myeloproliferative disorder
caused by the Philadelphia-positive chromosome deriving from
a translocation between chromosomes 22 and 9. The oncogenic
product of this aberrant chromosome is the constitutively
active tyrosine kinase BCR-ABL that is responsible for leukemic
cell growth, proliferation and survival driven by the dysregulation
of a large array of signal transduction pathways. Inhibition
of BCR-ABL with tyrosine kinase inhibitors proved to be an
efficient therapy of CML in the chronic phase. Unfortunately,
the impressive success of BCR-ABL inhibitors as front-line
therapy in CML has been tempered by problems of disease persistence
or relapse arising from different mechanisms, including mutations
in the kinase domain of the enzyme BCR-ABL and mechanisms
independent from BCR-ABL activity. Growing evidence has also
suggested a pivotal role of persistent leukemic cancer stem
cells, characterized by high self-renewal and pluripotency,
in CML maintenance and/or relapse. The present review deals
with the most recent advances in this challenging field and
focuses on the development of new drugs and therapeutic approaches
to eradicate the subtle and dangerous leukemic stem cells
responsible for maintaining and sustaining tumor growth.
[Back to top]
Multifaceted Mechanisms for Cell Survival and Drug
Targetingin Chronic Myelogenous Leukemia
Junya Kuroda, Yuji Shimura, Mio Yamamoto-Sugitani, Nana
Sasaki and Masafumi Taniwaki
[FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00085]
Treatment outcomes for chronic myelogenous leukemia (CML)
have shown major improvements as a result of the development
of the tyrosine kinase inhibitors (TKIs) imatinib, nilotinib
and dasatinib for the disease-specific molecular target BCR-ABL1
tyrosine kinase (TK), but a cure of CML byBCR-ABL1 TKIs has
been rarely achieved. CML cells are protected from cytotoxic
insults, including those by TKIs, through various collaborative
BCR-ABL1-mediated and -independentmechanisms, as well as cell-intrinsic
and -extrinsic molecular mechanisms. These protective mechanisms
include overlapping cell signaling pathways for normal hematopoietic
proliferation, modulation of molecules associated with the
BCL2 family protein-regulated programmed cell death pathway,
autophagic cell protection capability, bone marrow environment-mediated
cell protective signaling,abnormally upregulated genetic instability
and other BCR-ABL1-independent kinase activities. To develop
a more effective treatment strategy for a cure by means of
total leukemic cell killing, a thorough understanding of how
CML cells survive and resist cytotoxic insults is essential.
In this article, we review current knowledge about multifaceted
BCR-ABL1-related and -unrelated mechanisms for survival and
death of CML cells and present suggestions for the development
of new therapeutic strategies for complete elimination of
residual CML cells during TKI treatment.
[Back to top]
Antitumor effects of interferon-alpha on cell growth
and metastasis in human nasopharyngeal carcinoma
Xiong Liu, Juan Lu, Ming-Liang He, Zhi Li, Bao Zhang,
Li-Hui Zhou, Qi Li, Gang Li, Lu Wang, Wen-Dong Tian, Ying
Peng and Xiang-Ping Li
[FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00086]
Nasopharyngeal carcinoma (NPC) is a highly malignant and frequently
metastasized tumor, and the prognosis is very poor when distant
metastases occur. Recently, immunotherapy is becoming a promising
therapeutic approach. Interferon-α
(IFN-α)
represents the cytokines exhibiting the longest record of
use in clinical oncology. In this study, we examined the antitumor
effects of IFN-α1b
on NPC. The results showed that recombinant human IFN-α1b
(hIFN-α1b)
suppressed cell growth, induced a G1-phase cell cycle arrest
in vitro, increased the expression of p16
and pRb, and decreased the expression of CCND1 and CDK6. In
vivo analyses showed that either recombinant adeno-associated
virus (rAAV)-IFN-α1b
or hIFN-α1b
treatment inhibited tumor growth and metastasis, reduced intratumoral
microvessel density, increased cell apoptosis and necrosis,
and induced prolonged survival. Notably, rAAV-IFN-α1b
or hIFN-α1b
treatment led to significantly higher serum levels of IL-12
and GM-CSF in mice compared to respective controls. Our findings
suggest that IFN-α1b
acts as a multifunctional antitumor agent in NPC, which may
have important therapeutic implications.
[Back to top]
Editorial: Novel and emerging drugs
for leukemias
Tadeusz Robak
[BSP/CCDT/E-Pub/00087]
For the last twenty years, significant progress in molecular and cellular biology has resulted in a better characterization and understanding of the molecular abnormalities in leukemias. These achievements have provided new opportunities for the development of innovative, more effective drugs. Novel therapies are being evaluated both in pre-clinical studies and in early clinical trials. In this editorial, we demonstrate a brief review of the present insights into new therapeutic strategies for acute and chronic leukemias.
[Back to top]
Novel And Emerging Drugs For Acute Myeloid Leukemia
Eytan M. Stein and Martin S. Tallman
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00088]
Acute myeloid leukemia (AML) is a challenging disease to treat with the majority of patients dying from their illness. While overall survival has been markedly prolonged in acute promyelocytic leukemia (APL), survival in younger adults with other subtypes of AML have only modestly improved over the last twenty years. Physicians who treat AML eagerly await drugs like Imatinib for chronic myeloid leukemia, Cladribine for hairy cell leukemia, and Rituximab for non-Hodgkin Lymphoma which have had an important impact on improving outcome. Recent research efforts have focused on refining traditional chemotherapeutic agents to make them more active in AML, targeting specific genetic mutations in myeloid leukemia cells, and utilizing novel agents such as Lenalidomide that have shown activity in other hematologic malignancies. Here, we focus on reviewing the recent literature on agents that may assume a role in clinical practice for patients with AML over the next five years.
[Back to top]
Emerging therapies in chronic myeloid leukemia
Joanna Gora-Tybor
[FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00089]
Chronic myeloid leukemia (CML) therapy has dramatically changed in the last decade due to the introduction of tyrosine kinase inhibitors(TKIs) - imatinib, nilotinib and dasatinib. Despite the significant prolongation of overall survival ofCML patients there is still room for improvement. Approximately 20-25% of patients initially treated with imatinib will need alternative therapy, due to drug resistance which is often caused by the appearance of clones expressing mutantforms of BCR-ABL. Second generation TKIs dasatinib and nilotinib have shown promising results in imatinib-resistant or intolerant CML patients, but arenot active against CML clones with highly resistant T315I mutation. In recent years the special attention is put on small pool of leukemic stem cells which may contribute to the persistence of the leukemia. This article provides a review of preclinical and clinical data concerning the most promising new directions in CML treatment, with special emphasis on new drugs active in T315I mutation and compounds affecting leukemic stem cells.
[Back to top]
Novel and emerging drugs for rarer chronic lymphoid leukaemias
Estella Matutes
[Purchase Article] [BSP/CCDT/E-Pub/00090]
Rarer chronic lymphoid leukaemias represent a challenge to the clinicians due to the limited information on their pathogenesis, difficulties on setting up prospective clinical trials and to their refractoriness to drugs used in the most common form of chronic lymphocytic leukaemia (CLL). In this review all these issues are addressed in three B-cell leukaemias: B-cell prolymphocytic leukaemia (B-PLL), hairy cell leukaemia (HCL) and HCL-variant and three T-cell leukaemias: T-cell prolymphocytic leukaemia (T-PLL), T-cell large granular leukaemia (T-cell LGLL) and adult T-cell leukaemia lymphoma (ATLL). Data will be presented on the natural history, current therapies and emerging drugs potentially useful in the treatment of patients with these leukaemias. Emphasis is made on: 1- the novel agents targeting a variety of B and T-cell antigens expressed in the surface of the leukaemic cells; these are either unconjugated monoclonal antibodies (McAb) such as Rituximab (anti-CD20), the second and third generation of anti-CD20 McAbs, Alemtuzumab (anti-CD52), Siplizumab (anti-CD2), Daclizumab (anti-CD25) and KW-0761, an anti-chemokine receptor 4 (CCR4) or McAbs conjugated to toxins such as CD22 linked to the pseudomonas exotoxin or radiolabelled McAb; 2- the use of new purine nucleosides such as nelarabine and 3- agents targeting deregulated genes in the leukaemic cells from these diseases such as the Poly (ADP-ribose) polymerase (PARP) Olarapib in T-PLL with deregulation of the ataxia telangiectasia mutated (ATM) gene. Data of phase I and II clinical studies with these agents as well as the potential and current use of other drugs is outlined.
[Back to top]
Novel and emerging drugs for acute lymphoblastic leukemia
Ewa Lech-Maranda and Wojciech Mlynarski
[FULL-TEXT
INQUIRY] [BSP/CCDT/E-Pub/00091]
Over the past several decades the important progress has been made in the management of acute lymphoblastic leukemia (ALL), especially among children. However, in adult patients reported cure rates seldom exceeded 40%, despite the use of hematopoietic stem-cell transplantation in many cases. Conventional chemotherapy is toxic and ineffective. Therefore, new treatment options and risk-adapted therapies are needed to improve the outcome of ALL patients. This review is focused on new systemic treatment modalities, such as nucleoside analogues, purine synthetase inhibitors, monoclonal antibodies, tyrosine kinase inhibitors and other agents targeting molecular pathways that are aimed to benefit patients and improve the outcome of their treatment.
[Back to top]
Pioglitazone Prevents Smoking Carcinogen-Induced Lung Tumor Development In Mice
Ming-Yue Li, Angel WY Kong, Huiling Yuan, Lily T Ma, Michael K.Y. Hsin, Innes YP Wan, Malcolm J Underwood and George G Chen
[Purchase Article] [BSP/CCDT/E-Pub/00092]
Pioglitazone (PGZ), a synthetic peroxisome proliferator-activated receptor gamma (PPARγ) ligand, is known to have anti-tumor activity by inducing tumor cell apoptosis. However, it is unknown whether it can be used to prevent smoking carcinogen-induced lung tumor development. We induced mouse lung tumors using smoking carcinogen 4-methylnitrosamino-l-3-pyridyl-butanone (NNK). PGZ was given at two early stages before the tumor formation. The role and the functional mechanism of PGZ were investigated in the development of mouse pulmonary tumors. The tumor development was monitored and PPARγ activity and endogenous PPARγ ligands 15(S)-HETE, 13(S)-HODE were determined. The application of PGZ before alveolar hyperplasia formation (Group NPa) and at the early phase of alveolar hyperplasia formation (Group NPb) significantly prevented the lung tumor development especially in Group NPb mice (all p<0.05). PGZ not only prevented the NNK-mediated reduction of endogenous ligands 15(S)-HETE and 13(S)-HODE, but also increased 13(S)-HODE level in Group NPb mice. PPARγ transcriptional activity was increased in NNK-stimulated lung tissues when PGZ was given. The in vivo results were confirmed in the human lung cancer cells, which showed that PGZ induced lung cancer cell apoptosis through up-regulating nuclear PPARγ expression, inducing PPARγ transcriptional activity and increasing the levels of PPARγ ligands in NNK-treated cells. The early application of PGZ is able to prevent NNK-induced lung tumor development through maintaining the level of endogenous PPARγ ligands 15(S)-HETE and 13(S)-HODE and activation of PPARγ.
[Back to top]
Structural Comparison of the Interaction of Tubulin with Various Ligands Affecting Microtubule Dynamics
Emilia Stec-Martyna, Marco Ponassi, Mariangela Miele, Stefania Parodi, Lamberto Felli and Camillo Rosano
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00093]
Microtubules (MTs), which are highly dynamic assemblies of the protein tubulin, play important and diverse roles in eukaryotic cells. MT dynamics are regulated during the cell cycle by interacting with a large number of endogenous cellular regulators. In addition, many anti-tumour drugs and natural ligands that interact directly with tubulin are able to either stabilise or destabilise MTs and to disrupt the normal dynamics. Herein, we compare the structures of tubulin when complexed with different ligands in order to analyse: (i) various binding-sites of the protein and different positions of ligands within the microtubule (ii) the diverse effect on the microtubule dynamics. The structures and data given are essential for understanding tubulin-ligand interactions and their influence on the regulation of the microtubule system.
[Back to top]
Cyclooxygenase-2 (COX-2) Mediates Arsenite Inhibition of UVB-induced Cellular Apoptosis in Mouse Epidermal Cl41 cells
Zhenghong Zuo, Weiming Ouyang, Jingxia Li, Max Costa and Chuanshu Huang
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00094]
Inorganic arsenic is an environmental human carcinogen, and has been shown to act as a co-carcinogen with solar ultraviolet (UV) radiation in mouse skin tumor induction even at low concentrations. However, the precise mechanism of its co-carcinogenic action is largely unknown. Apoptosis plays an essential role as a protective mechanism against neoplastic development in the organism by eliminating genetically damaged cells. Thus, suppression of apoptosis is thought to contribute to carcinogenesis. It is known that cyclooxygenase-2 (COX-2) can promote carcinogenesis by inhibiting cell apoptosis under stress conditions; and our current studies investigated the potential contribution of COX-2 to the inhibitory effect of arsenite in UV-induced cell apoptosis in mouse epidermal Cl41 cells. We found that treatment of cells with low concentration (5 μM) arsenite attenuated cellular apoptosis upon UVB radiation accompanied with a co-inductive effect on COX-2 expression and nuclear factor-κB (NFκB) transactivation. Our results also showed that the COX-2 induction by arsenite and UVB depended on an NFκB pathway because COX-2 co-induction could be attenuated in either p65-deficient or p50-deficient cells. Moreover, UVB-induced cell apoptosis could be dramatically reduced by the introduction of exogenous COX-2 expression, whereas the inhibitory effect of arsenite on UVB-induced cell apoptosis could be impaired in COX-2 knockdown C141 cells. Our results indicated that COX-2 mediated the anti-apoptotic effect of arsenite in UVB radiation through an NFkB-dependent pathway. Given the importance of apoptosis evasion during carcinogenesis, we anticipated that COX-2 induction might be at least partially responsible for the co-carcinogenic effect of arsenite on UVB-induced skin carcinogenesis.
[Back to top]
High Cxcr4 Expression Correlates With Sunitinib Poor Response In Metastatic Renal Cancer
D’Alterio Crescenzo, Portella Luigi, Ottaiano Alessandro, Rizzo Mimma, Carteni Giacomo, Pignata Sandro, Facchini Gaetano, Perdonà Sisto, Di Lorenzo Giuseppe, Autorino Riccardo, Franco Renato, La Mura Anna, Nappi Oscar, Castello Giuseppe and Scala Stefania
[Purchase Article] [BSP/CCDT/E-Pub/00095]
Background: Almost 30% of the sunitinib-treated patients for metastatic renal carcinoma (mRCC) do not receive a clinical benefit. Convincing evidences demonstrated a cross talk between the VEGF and CXCR4 pathways. It was hypothesized that CXCR4 expression in primary renal cancer could predict sunitinib responsiveness.
Patients and Methods: In this exploratory study sixty-two mRCC patients receiving sunitinib as first-line treatment were evaluated for CXCR4 expression through immunohistochemistry (IHC). Correlations between CXCR4 expression, baseline patients and tumour characteristics were studied by contingency tables and the chi-square test. Univariable analysis was performed with the log-rank test, and the Cox model was applied for multivariable analysis.
Results: The objective response rate of sunitinib first-line therapy was 35.5% (22/62) with a disease control rate (response and stable disease) of 62.9% (39/62). CXCR4 expression was absent/low in 30 (48.4%), moderate in 17 (27.4%), and high in 15 (24.2%) tumors respectively. Low or absent CXCR4 expression predicted response to sunitinib therapy. Moreover, Fuhrman grading and concomitant, CXCR4 and Fuhrman grading, strongly predicted sunitinib first line therapy responsiveness on progression-free survival and overall survival.
Conclusions: High CXCR4 expression correlates with sunitinib poor response in metastatic renal cancer.
[Back to top]
Growth Suppression and Mitotic Defect Induced by JNJ-7706621, an Inhibitor of Cyclin-Dependent Kinases and Aurora Kinases
Aya Matsuhashi, Takatoshi Ohno, Masashi Kimura, Akira Hara, Masanao Saio, Akihito Nagano, Gou Kawai, Mitsuru Saitou, Iori Takigami, Kazunari Yamada, Yukio Okano and Katsuji Shimizu
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00096]
Aurora kinases and cyclin-dependent kinases, which play critical roles in the cell cycle and are frequently overexpressed in a variety of tumors, have been suggested as attractive targets for cancer therapy. JNJ-7706621, a recently identified dual inhibitor of these kinases, is reported to induce cell cycle arrest, endoreduplication, and apoptosis. In the present study, we further investigated the molecular mechanisms underlying these effects. The inhibitor arrested various cells at G2 phase at low concentration, and at both G1 and G2 phases at high concentration. JNJ-7706621 did not prevent localization of Aurora A to the spindle poles, but did inhibit other centrosomal proteins such as TOG, Nek2, and TACC3 in early mitotic phase. Similarly, the drug did not prevent localization of Aurora B to the kinetochore, but did inhibit other chromosomal passenger proteins such as Survivin and INCENP. In the cells exposed to JNJ-7706621 after nocodazole release, Aurora B, INCENP, and Survivin became relocated to the peripheral region of chromosomes, but Plk1 and Prc1 were localized on microtubules in later mitotic phase. Treatment of nocodazole-synchronized cells with JNJ-7706621 was able to override mitotic arrest by preventing spindle checkpoint signaling, resulting in failure of chromosome alignment and segregation. Injection of the drug significantly inhibited the growth of TC135 Ewing’s sarcoma cells transplanted into athymic mice by cell cycle arrest and apoptosis. JNJ-7706621 is a unique inhibitor regulating cell cycle progression at multiple points, suggesting that it could be useful for cell cycle analysis and therapy of various cancers, including Ewing’s sarcoma.
[Back to top]
Lycopene modulation of molecular targets affected by smoking exposure
Paola Palozza, Rossella Simone, Assunta Catalano, Marco Russo and Volker Böhm
[Purchase Article] [BSP/CCDT/E-Pub/00097]
Increasing evidence indicates that tomato lycopene may be an ideal candidate in protecting from cancer risk related to smoking exposure. The carotenoid shows potent redox-properties by which it decreases the reactive oxygen species (ROS) generated by smoke and modulates redox-sensitive cell targets, including protein tyrosine phosphatases, protein kinases, MAPKs and transcription factors. Moreover, it counteracts the effects of smoke on carcinogen-bioactivating enzymes and on molecular pathways involved in cell proliferation, apoptosis and inflammation. Lycopene also inhibits smoke-stimulated IGF-signalling and smoke-induced DNA adducts. Some of these actions may be mediated by its oxidative metabolites and may be synergistically enhanced by the presence of other antioxidant nutrients. This review summarizes the background information about the interactions of lycopene with smoke in experimental models and presents the most current knowledge with respect to lycopene role in smoke-related diseases.
[Back to top]
Polysialyltransferase: a new target in metastatic cancer
Robert A. Falconer, Rachel J. Errington, Steven D. Shnyder, Paul J. Smith and Laurence H. Patterson
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00098]
Polysialic acid (polySia) is a carbohydrate polymer critical for neuronal cell migration and axon pathfinding in embryonic development. Besides brain regions requiring persistent neuronal plasticity, polySia is essentially absent from the adult body. However, polySia is aberrantly re-expressed on many tumours, where it decorates the surface of NCAM (neuronal cell adhesion molecule) and modulates cell adhesion, migration and invasion. PolySia-NCAM expression is strongly associated with poor clinical prognosis and correlates with aggressive and invasive disease in many cancers, including lung cancer, neuroblastoma and gliomas. The synthesis of polySia is mediated by two polysialyltransferases (polySTs), ST8SiaIV (PST) and particularly ST8SiaII (STX) in cancer cells. The demonstration that polyST knock-down negates events associated with tumour cell dissemination indicates that PST and STX are validated targets. Selective inhibition of polySTs therefore presents a therapeutic opportunity to inhibit tumour invasion and metastasis.
[Back to top]
Inhibition of Protein N-Myristoylation: A Therapeutic Protocol in Developing Anticancer Agents
U. Das, S. Kumar, J. R. Dimmock and R. K. Sharma
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00099]
N-myristoyltransferase (NMT) is an essential eukaryotic enzyme which catalyzes the transfer of the myristoyl group to the terminal glycine residue of a number of proteins including those involved in signal transduction and apoptotic pathways. Myristoylation is crucial for the cellular proliferation process and is required for the growth and development in a number of organisms including many human pathogens and viruses. Targeting the myristoylation process thus has emerged as a novel therapeutic strategy for anticancer drug design. The expression/activity of NMT is considerably elevated in a number of cancers originating in the colon, stomach, gallbladder, brain and breast and attenuation of NMT levels has been shown to induce apoptosis in cancerous cell lines and reduce tumor volume in murine xenograft models for cancer. A focus of current therapeutic interventions in novel cancer treatments is therefore directed at developing specific NMT inhibitors. The inhibition of the myristoyl lipidation process with respect to cancer drug development lies in the fact that many proteins involved in oncogenesis such as src and various kinases require myristoylation to perform their cellular functions. Inhibiting NMT functions to control malignancy is a novel approach in the area of anticancer drug design and there are rapidly expanding discoveries of synthetic NMT inhibitors as potential chemotherapeutic agents to be employed in the warfare against cancer. The current review focuses on developments of various chemical NMT inhibitors with potential roles as anticancer agents.
[Back to top]
Novel and emerging drugs for chronic lymphocytic leukemia
Susanne Isfort, Paula Cramer and Michael Hallek
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00100]
During the last decades advanced treatment options for chronic lymphocytic leukemia have enabled the shift from rather ineffective palliative treatment to therapies that are aiming for long lasting complete remission and prolongation of survival. This remarkable progress was achieved by combining conventional chemotherapy with monoclonal antibodies such as rituximab and alemtuzumab.
Despite this improvement, CLL remains an incurable disease and all patients will eventually relapse and become refractory to treatment. Allogeneic stem cell transplantation is the only curative option but is feasible only in a minority of patients due to the comorbidity and impaired physical fitness of many patients, since the mean age at first diagnosis lies between 70 and 75 years. Therefore, novel non-toxic therapeutic agents are needed, particularly for patients with comorbidities or high-risk cytogenetic abnormalities.
Research in the field of CLL and growing understanding of the pathogenesis of B-cell lymphomas has produced a wide variety of new substances for different targets, e.g. different novel monoclonal antibodies, immunomodulatory agents and inhibitors targeting different kinases of B-cell receptor signalling cascade, such as Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K).
This article reviews novel drugs that were recently developed for the use in CLL. The agents discussed in this article were selected for having shown preliminary evidence of clinical activity.
[Back to top]
Acid ceramidase as a chemotherapeutic target to overcome resistance to the antitumoral effect of choline kinase α inhibition
Ana Ramírez de Molina, Ana de la Cueva, Rosario Machado-Pinilla, Vanessa Rodríguez-Fanjul, Teresa Gómez del Pulgar, Arancha Cebrián, Rosario Perona and Juan Carlos Lacal
[Purchase Article] [BSP/CCDT/E-Pub/00101]
We have analyzed the response of primary cultures derived from tumour specimens of non small cell lung cancer (NSCLC) patients to choline kinase α (ChoKα inhibitors. ChoKα inhibitors have been demonstrated to increase ceramides levels specifically in tumour cells, and this increase has been suggested as the mechanism that explain its proapoptotic effect in cancer cells. Here, we have investigated the molecular mechanism associated to the intrinsic resistance, and found that other enzyme involved in lipid metabolism, acid ceramidase (ASAH1), is specifically upregulated in resistant tumours. NSCLC cells with acquired resistance to ChoKα inhibitors also display increased levels of ASAH1. Accordingly, ASAH1 inhibition synergistically sensitizes lung cancer cells to the antiproliferative effect of ChoKα inhibitors. Thus, the determination of the levels of ASAH1 predicts sensitivity to targeted therapy based on ChoKα specific inhibition and represents a model for combinatorial treatments of ChoKα inhibitors and ASAH1 inhibitors. Considering that ChoKα inhibitors have been recently approved to enter Phase I clinical trials by the Food and Drug Administration (FDA), these findings are anticipating critical information to improve the clinical outcome of this family of novel anticancer drugs under development.
[Back to top]
A molecular signature for oncogenic BRAF in human colon cancer cells is revealed by microarray analysis
Tobias Joyce, Eftychia Oikonomou, Vivian Kosmidou, Eleni Makrodouli, Ioannis Bantounas, Spiros Avlonitis, Georgios Zografos and Alexander Pintzas
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00102]
Sporadic colorectal cancer develops through a number of functional mutations. Key events are mutually exclusive mutations in BRAF or RAS oncogenes. Signatures for BRAF oncogene have been revealed in melanoma. In a previous study we have reported a molecular signature for HRAS and KRAS mutations in colorectal cell lines that also showed an EMT phenotype for HRAS.
In this study we report a molecular profile for a BRAF oncogenic mutation BRAFV600E in colon using the Illumina 45,000 gene microarray. Key differentially expressed genes have been identified from the array analysis further verified by qPCR analysis.
Ingenuity pathway analysis such as microsatelite instability, kinase signalling, apoptosis, WNT and Integrin signalling is presented. MutBRAF transforms cells through cross talk with developmental pathways Hedgehog and Wnt, as well as by deregulation of colorectal cancer related kinase pathways, like PI3K.
Differential gene expression of BRAFV600E in colon as compared to those associated with RAS oncogenes is presented, as well as similarities and differences between oncogenic BRAF signatures in colon as compared to thyroid and melanoma are highlighted. Novel selected genes/pathways are validated in cell lines and clinical samples bearing BRAFV600E and may serve as markers/targets for personalised diagnosis/therapy/resistance of colorectal cancer.
[Back to top]
Polysialyltransferase: a new target in metastatic cancer
Robert A. Falconer, Rachel J. Errington, Steven D. Shnyder, Paul J. Smith and Laurence H. Patterson
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00103]
Polysialic acid (polySia) is a carbohydrate polymer critical for neuronal cell migration and axon pathfinding in embryonic development. Besides brain regions requiring persistent neuronal plasticity, polySia is essentially absent from the adult body. However, polySia is aberrantly re-expressed on many tumours, where it decorates the surface of NCAM (neuronal cell adhesion molecule) and modulates cell adhesion, migration and invasion. PolySia-NCAM expression is strongly associated with poor clinical prognosis and correlates with aggressive and invasive disease in many cancers, including lung cancer, neuroblastoma and gliomas. The synthesis of polySia is mediated by two polysialyltransferases (polySTs), ST8SiaIV (PST) and particularly ST8SiaII (STX) in cancer cells. The demonstration that polyST knock-down negates events associated with tumour cell dissemination indicates that PST and STX are validated targets. Selective inhibition of polySTs therefore presents a therapeutic opportunity to inhibit tumour invasion and metastasis.
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Emerging roles for modulation of microRNA signatures in cancer chemoprevention
Karthik Neelakandan, Pradeesh Babu and Sujit Nair
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00104]
miRNAs are small endogenous non-coding RNAs, approximately 21-nucleotides in length, which are shown to regulate an array of cellular processes such as differentiation, cell cycle, cell proliferation, apoptosis, and angiogenesis which are important in cancer. miRNAs can function as both tumor promoters (oncomiRs) or tumor suppressors by their ability to target numerous biomolecules that are important in carcinogenesis. Aberrant expression of miRNAs is correlated with the development and progression of tumors, and the reversal of their expression has been shown to modulate the cancer phenotype suggesting the potential of miRNAs as targets for anti-cancer drugs. Several chemopreventive phytochemicals like epigallocatechin-3- gallate, curcumin, isoflavones, indole-3-carbinol, resveratrol, and isothiocyanate have been shown to modulate the expression of numerous miRNAs in cancer cells that led to either abrogation of tumor growth or sensitization of cancer cells to chemotherapeutic agents. This review focuses on the putative role(s) of miRNAs in different aspects of tumorigenesis and at various stages of early drug discovery that makes them a promising class of drug targets for chemopreventive intervention in cancer. We summarize the current progress in the development of strategies for miRNA-based anti-cancer therapies. We also explore the modulation of miRNAs by various cancer chemopreventive agents and the role of miRNAs in drug metabolism. We will discuss the role of miRNAs in cancer stem cells and epithelial-to-mesenchymal transition; and talk about how modulation of miRNA expression relates to altered glycosylation patterns in cancer cells. In addition, we consider the role of altered miRNA expression in carcinogenesis induced by various agents including genotoxic and epigenetic carcinogens. Finally, we will end with a discussion on the potential involvement of miRNAs in the development of cancer chemoresistance.Taken together, a better understanding of the complex role(s) of miRNAs in cancer may help in designing better strategies for biomarker discovery or drug targeting of miRNAs and/or their putative protein targets.
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The impact of proteomics in the understanding of the molecular basis of paclitaxel-resistance in ovarian tumors
Daniele Vergara, Andrea Tinelli, Anna Iannone and Michele Maffia
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00105]
The current therapy for ovarian cancer has advanced from alkylating agents, to a combination of carboplatinum and paclitaxel offering increased survival. Although most patients respond to this first-line therapy, initially, the majority of these patients relapse within 2 years. The mechanisms responsible for acquired drug resistance in ovarian cancer have been elucidated only in part. They include i) enhanced drug export, ii) activation/inhibition of intracellular signalling pathways, iii) molecular alterations in tubulin isotype composition. A better understanding of these mechanisms is needed, in order to develop new approaches, aimed at overcoming resistance to anticancer agents, and to reveal the complexity of causes, which contribute to drug resistance. In this review we offer an updated overview of proteomic studies on the molecular mechanisms of paclitaxel resistance. These proteomic studies also identify potential targets for modulating drug resistance, that could be predictive of response to chemotherapy in ovarian carcinomas.
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Increased Expression of Matrix Metalloproteinases Mediates Thromboxane A2-Induced Invasion in Lung Cancer Cells
Xiuling Li and Hsin-Hsiung Tai
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00106]
Thromboxane A2 receptor (TP) has been shown to play an important role in multiple aspects of cancer development including regulation of tumor growth, survival and metastasis. Here we report that TP mediates cancer cell invasion by inducing expression of matrix metalloproteinases (MMPs). TP agonist, I-BOP, significantly elevated MMP-1, MMP-3, MMP-9 and MMP-10 mRNA levels in A549 human lung adenocarcinoma cells overexpressing TPα or TPβ. The secretion of MMP-1 and MMP-9 in conditioned media was determined using Western blot analysis and zymographic assay. Signaling pathways of I-BOP-induced MMP-1 expression were examined in further detail as a model system for MMPs induction. Signaling molecules involved in I-BOP-induced MMP-1 expression were identified by using specific inhibitors including small interfering (si)-RNAs of signaling molecules and promoter reporter assay. The results indicate that I-BOP-induced MMP-1 expression is mediated by protein kinase C (PKC), extracellular signal-regulated kinase (ERK)-activator protein-1(AP-1) and ERK-CCAAT/enhancer-binding protein β (C/EBPβ) pathways. I-BOP-induced cellular invasiveness of A549 cells expressing TPα or TPβ was determined by invasion assay. GM6001, a general inhibitor of MMPs, decreased basal and I-BOP-induced cell invasion. Knockdown of MMP-1 and MMP-9 by their respective siRNA partially reduced I-BOP-stimulated cell invasion suggesting that other MMPs induced by I-BOP were also involved. Our studies establish the relationship between TP and MMPs in cancer cell invasion and suggest that the Thromboxane A2 (TXA2)-TP signaling is a potential therapeutic target for cancer invasion and metastasis.
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Anti-tumor effect of AlkB homolog 3 knockdown in hormone-independent prostate cancer cells
Kazuhisa Koike, Yuko Ueda, Hiroaki Hase, Kaori Kitae, Yasuyuki Fusamae, Seiko Masai, Takaaki Inagaki, Yasuka Saigo, Shinji Hirasawa, Kazuhiro Nakajima, Ikumi Ohshio, Yasutake Makino, Noboru Konishi, Hiroshi Yamamoto and Kazutake Tsujikawa
[FULL-TEXT INQUIRY] [BSP/CCDT/E-Pub/00107]
Castrate resistant prostate cancer (CRPC) is a disease that is resistant to both hormone therapy and chemotherapy. At present, no curative therapy for CRPC has been established. Therefore, it is necessary to determine a novel molecular target for the development of therapeutic agents. We previously reported that AlkB homolog 3 (ALKBH3) is highly expressed in prostate cancer but not in benign prostatic hyperplasia or in normal prostate epithelium and that the expression levels of ALKBH3 protein are significantly correlated with the hormone-independent state of prostate cancer. Moreover, ALKBH3 regulates the invasion of prostate cancer cells via the regulation of matrix metalloproteinase 9. Here, we show that ALKBH3 gene silencing markedly induces apoptosis in hormone-independent prostate cancer cell line DU145 but not in the normal prostate epithelial cell line PNT2. Moreover, the in vivo tumorigenicity of DU145 cells was significantly inhibited by the administration of ALKBH3 siRNA. Furthermore, the anchorage-independent growth of DU145 cells was inhibited by ALKBH3 knockdown and promoted by ALKBH3 overexpression, significantly. ALKBH3 shRNA-expressing prostate cancer cells formed significantly smaller tumors than those of control shRNA transfectants in an in vivo xenograft model. These findings suggest that ALKBH3 is a promising target molecule for the development of CRPC therapeutic agents.
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