Most Cited Articles:

Abstracts


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Apoptotic Signaling in Pancreatic Cancer - Therapeutic Application (Supplemental Data)
Felix Ruckert, Christian Pilarsky, Hans-Detlev Saeger, Robert Grutzmann

Pancreatic cancer is an exceptionally devastating and incurable disease, the treatment of which has largely been unsuccessful due to the higher resistance of pancreatic tumor cells to oncologic treatment. PDAC cells have accumulated different molecular mechanisms, which enable survival against cytotoxic therapies. Defects of the apoptosis pathway play a crucial role.

For the last 10 years, many investigations were underway to get insights into the details of the anti-apoptotic mechanisms of PDAC cells. The present review provides a comprehensive description of the molecular signaling of the apoptotic pathway, an incentive on the potential pathogenetic role of different molecular defects on existing oncologic treatments and an appraisal of the most recent therapeutic strategies applied at a cell biochemical level.


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Two Diseases with One Hit: Inhibiting a Potential Diabetes Target to Reduce Cancer Risk and to Improve Anti-Cancer Therapy
Nagendra K. Prasad

Obesity is a well-recognized cancer risk factor. The increase in risk for colorectal, endometrial, breast and esophageal cancers associated with obesity ranges from 1.5- to as much as 3-fold. Obese patients develop more aggressive cancers that are less responsive to treatment. Here, we review the available data on an obesity-linked gene, SH2-domaincontaining inositol 5-phosphatase-2 (SHIP2), in light of new experimental and clinical evidence of its pro-oncogenic role. A putative diabetes drug target, SHIP2 is an important negative regulator of insulin signaling that acts downstream of phosphoinositide 3-kinase (PI3-kinase). In mice, SHIP2 levels are increased by a high-fat diet, and its knockout prevents diet-induced obesity. Taking together these findings, we propose that SHIP2 is a potential anti-cancer target with a high therapeutic index owing to its cancer-specific overexpression and/or differential function combined with the absence of major untoward effects upon its loss of function in normal cells. We compare and contrast the pro-oncogenic function of SHIP2 with the current understanding of cancer-relevant functions of PTEN and PTP-1B, two negative regulators of insulin function. The provocative idea that a negative regulator of insulin function will positively influence oncogenesis presents the intriguing possibility that its inhibition will be a beneficial strategy for two major therapeutic areas: metabolic diseases (such as obesity and diabetes) and cancer.


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Telomerase and Survivin in Colorectal and Pancreatic Cancer - Biomarkers of Life and Death in the Balance Between Proliferation and Apoptosis
Kjetil Soreide

Colorectal and pancreatic cancer represent two major health concerns in their own right - the first for being one of the most prevalent cancers in the western world, and the latter for being one of the most lethal of all human cancers. While progress has been made in cancer research and tumor understanding in general, and for colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) in particular, still thousands of lives are lost to these two diseases annually. Obviously, the search for new molecular markers and pathways that will lead to better and earlier diagnostics, with potential for better and more efficient therapeutic interventions is direly needed.

A general overview of cancer hallmarks, with focus on proliferation and apoptosis is given in this mini-review. The molecular role of the telomere function and the universal tumor-antigen survivin, with regards to CRC and PDAC progression and development is discussed. These two markers may hold universal cancer therapeutic potential, also for CRC and PDAC.


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Cancer Therapeutics: Emerging Targets and Trends
Mohd. Fahad Ullah

Several decades of investigation concerning the cause and cure of cancer have revealed major discrepancies in the response of different cancer types towards a particular therapy and therefore a need for more effective approaches has been conceived. It is known that cancer development irrespective of its origin occurs due to the compromises that normal cells make in critical pathways, thereby allowing to transform into a tumor. It is thus conceivable that the most effective cancer therapy requires multiple targeting of molecular alterations responsible for malignant transformation. In this context, the development of combinational therapies aimed at multi-cornered attack on cancer cells is of particular significance. The present article is a brief review of the novel trends emerging in cancer therapeutics with special emphasis on epigenetic therapy, cancer stem cell therapy, modern radiotherapy, target based cancer therapy and polyphenol therapy.


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The Role of Nucleoside Transport in the Antineoplastic Activity of Purine Nucleoside Chemotherapeutic Agents
Carol E. Cass, Karen M. King

Purine nucleoside analogues are extensively used in the treatment of malignancies and viral diseases. For example, cladribine and fludarabine are two purine nucleoside analogues that have activity in the treatment of chronic lymphocytic leukemias. These chemotherapeutic agents exert their cytotoxic actions through interactions with intracellular targets. Due to their hydrophilic nature, many purine nucleoside analogues do not readily diffuse across cell membranes at therapeutic concentrations. The presence or absence of mediated transport systems will therefore have an impact on their pharmacological activities.

There are two families of nucleoside transporters with members in human (h) cells and tissues: the equilibrative nucleoside transporters (hENTs) and the concentrative nucleoside transporters (hCNTs). These transporter proteins mediate the uptake of both physiologic nucleosides and nucleoside analogue chemotherapeutic agents. It has been documented that permeant specificity, tissue distribution and cellular localization of these transporters contribute to the antineoplastic activity of the purine nucleoside analogues. This article will review current knowledge of the role of nucleoside transport proteins in the cytotoxic actions of purine nucleoside analogues.


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Clinical Development of MET Targeted Therapy For Human Cancer
Nima Tirgan, Zhe Tang, Patrick C. Ma

MET is a member of the semaphorins, plexins and MET/RON receptor family, which is stimulated by the ligand hepatocyte growth factor (HGF) and uniquely regulates a wide range of cellular functions. When dysregulated and activated, as in the case of human cancers with MET amplification or overexpression, mutation or alternative splicing, it has been implicated to play pivotal role in human tumor cell progression and metastasis. MET-HGF signal path has been shown to be attractive therapeutic target for human cancer novel therapy. In recent years, substantial progresses have been achieved to advance MET-HGF inhibitory strategies from the bench-top preclinical studies to clinical trial studies. Targeting agents being developed include not only various small molecule MET inhibitors, but also specific anti-MET or anti- HGF antibodies. Current emerging knowledge of the kinases signaling cross-talk networks will eventually facilitate rational design of optimal treatment strategies combining MET inhibition with other inhibitors, such as erlotinib (against EGFR). In this review, we summarize the relevant MET receptor biology, mutations (especially non-kinase domain mutations) and other genomic alterations in human cancers. The strategies to inhibit MET-HGF as novel therapy in human cancer as well as agents undergoing clinical trial studies would be discussed. Finally, we also summarize the various challenges to be met, including predictive biomarkers identification, patient selection, and rational combinational treatment approaches.


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The Combination of Conventional Chemotherapy with New Targeted Therapy in Hematologic Malignancies: The Safety and Efficiency of Low- Dose Cytarabine Supports its Combination with New Therapeutic Agents in Early Clinical Trials
Hanne Fredly, Elisabeth Ersvaer, Camilla Stapnes, Bjorn Tore Gjertsen, Oystein Bruserud

Cytarabine (cytosine arabinoside) is commonly used in the treatment of hematologic malignancies, including both myeloid and lymphoid disorders. The cytotoxic effect of the drug depends on conversion to its triphosphate form in the targeted cells, and the intracellular levels of this active form depend on the balance between phosphorylating and dephosphorylating enzymes. The sensitivity to cytarabine-triphosphate induced cytotoxicity is in addition dependent on the balance between pro- and antiapoptotic signalling in the malignant cells, especially the balance between various members of the bcl-2 family. Even though differentiation induction has been claimed to be important in low-dose cytarabine, most clinical studies suggest that the cytotoxic affect is most important even in this therapeutic strategy. The clinical experience with the low-dose therapy is based on studies in hematological malignancies, mainly acute myeloid leukemia and myelodysplastic syndromes. These studies clearly document the clinical efficiency of low-dose therapy. However, even this low-dose strategy has a risk of severe hematological toxicity and eventually serious or fatal infections especially in elderly patients. Our understanding of the molecular mechanisms behind chemoresistance and chemosensitivity to cytarabine thereby forms the scientific basis for the design of future clinical studies where cytarabine can be combined with new targeted therapy. Low-dose cytarabine may then represent an efficient alternative with an acceptable toxicity even when combined with new anticancer agents in early clinical studies. However, the possibility of pharmacological interactions with the intracellular metabolism of cytarabine by these new agents has to be considered when combination regimens are designed.


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Tumor Systems Need to be Rendered Usable for a New Action-Theoretical Abstraction: The Starting Point for Novel Therapeutic Options
Albrecht Reichle

Background: A tumor system not only consists of diverse cell types but also comprises all components of action insofar that these components are oriented in terms of diverse cell types. Methods: Thus, it is necessary to decode paradox situations of cellular rationalization, deformation, and communication processes or, in other words, to uncover inconsistencies within tumor cell compartments or distinct topologies of aggregated action effects. Here, a theory may be helpful that discharges into an action-theoretical abstraction and simultaneously includes evolutionary tumor developments. In an evolutionary process, tumor cells may exploit the whole extent of the rationalization features of stroma cells to implement the functional diversity of systems behavior aimed at maintaining homeostasis, and robustness in tumor systems. The introduction of genomic/non-genomic systems-directed therapeutic approaches may allow both, the uncovering of systems topologies of aggregated action effects and the broadening of therapeutic options via systems-directed approaches. Results: (1) Tumor systems biology is now turning into a scientific co-subject. (2) Developing actiontheoretical systems terms with the corresponding conceptual equipment may contribute to the classification of tumor subsystems. (3) Systems-directed therapies may meet new therapeutic requirements, which might help to create therapeutic approaches that are specifically designed for the demand of tumor stages, corresponding systems stages. Conclusions: Therefore, patients would probably not have to be selected according to age and/or co-morbidities because of known adverse toxicities of standard therapies (maximal tolerable doses). In contrast, therapies may meet the (individual) tumor system's characteristics by a systems-orientated selection of biomodulatory acting agents. As shown, toxicities may be modest.