Current Medicinal Chemistry - Volume 25, Issue 22, 2018

Background: The incidence of pancreatic cancer (PC) is rising in parallel with the deaths caused by this malignant disease largely due to limited improvement in current treatment strategies. In spite of aggressive PC research, for the past three decades, there has been no significant improvement in the five-year survival for this cancer. Like many other cancers, it takes several years for normal pancreatic cells to transform into pancreatic precursor lesions and to further progress into invasive carcinoma. Hence there is a scope for the development of chemo-preventive strategies to inhibit/ delay/prevent progression of this disease into an advanced stage cancer. Objective: Chemoprevention of pancreatic cancer. Method: Review of published literature. Results and Conclusion: Availability of various genetically engineered mouse (GEM) models of PC has led to accelerated progress in understanding the disease and developing intervention strategies otherwise stalled for a long time. These GEM models spontaneously develop PC in a stepwise manner and mimic the disease etiology in humans. Understanding PC development from initiation to progression to metastasis is very important for early detection and prevention of PC. In this review, we focus on the current situation, the potential challenges, the progress in existing strategies and available opportunities as well as suggest key areas for research within the increasingly important area of pancreatic cancer chemoprevention.

Background: Pancreatic cancer management remains a major challenge to society. Poor prognosis results in dismal patient survival rates and quality of life post chemo/radiation therapies. Although progress has been made in drug development for targeting pancreatic cancer, accompanying issues of drug resistance renders it futile. While intake of fruits and vegetables in routine diets has been linked to reduced risk of pancreatic cancer, a wide variety of natural agents are being evaluated as adjuvant therapies in combination with frontline chemotherapeutics in pancreatic cancer clinical trials. Objective: This review highlights the emerging area of cancer chemoprevention with natural/ dietary compounds serving as novel agents possessing strong anticancer properties; these are pleiotropic agents targeting multiple pathways with minimal toxicity in normal tissue. Methods: We employed extensive literature search and considered all the relevant information presented in a concise, well-balanced and structured format. Results: Completed and ongoing human studies with natural agents have shown surprisingly successful rates for regulating pancreatic carcinogenesis. Combinatorial therapies with synthetic, approved drugs and natural agents not only improved the patient response rates, but also helped in overcoming drug resistance and inducing chemosensitivity to the resistant tumors, as opposed to monotherapies for pancreatic cancer chemoprevention. Conclusion: The current review focuses on the available chemotherapeutic drugs and their limitations, and moves on to discuss the wide realm of chemopreventive efficacy that the natural agents have to offer. It discusses the underlying mechanisms of action and available information, from extensive literature analysis, to highlight the novelty of these agents for their antitumor effects against pancreatic cancer.

Background: Pancreatic cancer is the fourth leading cause of cancer deaths with rising incidence and a high mortality rate. Smoking, psychological stress, diabetes, pancreatitis and alcohol abuse are known risk factors for pancreatic cancer. Objective: Targeting G protein-coupled receptor signaling for the prevention and therapy of pancreatic cancer. Method: Review of published literature. Results and Conclusion: All known risk factors for pancreatic cancer cause hyperactive cyclic adenosine monophosphate (cAMP) signaling via cancer stimulating Gαs-coupled beta-adrenergic and prostaglandin E2 receptors and/or by suppressing signaling via inhibitory Gαi-coupled GABAB-receptors. Psychological stress in mice promotes the progression of pancreatic cancer xenografts via stress neurotransmitter-mediated increase in betaadrenergic signaling and suppression of GABA while stress reduction inhibits pancreatic cancer by reversing these effects. The activation of Gαi-coupled GABAB-receptor signaling by treatment with GABA, inhibition of beta-adrenergic signaling by a beta-blocker and/or suppression of Gαs-coupled PGE2 receptor signaling by a cyclooxygenase (COX) inhibitor prevent the development and progression of pancreatic cancer induced in hamsters by carcinogenic nitrosamines and in transgenic mice. The re-purposing of cardiovascular therapeutics (beta-blockers, COX-2 inhibitors, Ca2+-channel blockers) that inhibit betaadrenergic and PGE2 signaling for pancreatic cancer intervention is problematic due to undesirable side effects under chronic treatment protocols. To avoid such side effects while effectively reducing excessive cAMP signaling, nutritional GABA supplementation or positive allosteric modulators (PAMs) of Gαi-coupled receptors (GABAB-Rs) currently in clinical trials for the treatment of addiction should be explored for pancreatic cancer intervention.

Background: Pancreatic cancer (PC) is considered an incurable disease due to late diagnosis, rapid spread and negligible response treatment methods, with a 5-year survival rate of only 7%. Hence, there is an urgency in developing novel strategies for PC prevention. This review is focused on discussing the challenges in understanding complex immune functions in tumor microenvironment and host-induced immune responses against tumors, selection of antigens for development of preventive vaccines, lessons from immunoprevention clinical trials and challenges in developing future vaccines. Methods: 65 original articles were referenced from various sources, based on immunoprevention or criteria pertaining to tumor antigens and immune responses in PC. All these articles were analyzed for the method details and results obtained, and the existing challenges were derived for successful development of clinical immunoprevention strategies. Results: The analysis of these articles and our experience with preclinical efficacy evaluations of various preventive approaches against PC helped in identifying specific tumor antigens as targets which can overcome tumor cell immune suppression. This review discussed the status of primary, secondary and tertiary preventive vaccines and reasons for failure of therapeutic vaccines. The key parameters for effective vaccination were identified, including stage of the disease for vaccination efficacy, use of appropriate animal models for development of preventive vaccines. Potential of chemopreventive agents as adjuvants in immunoprevention was discussed. This review identified new challenges for development of immunopreventive vaccines. Conclusion: This review analyzed various aspects of vaccine development for immunoprevention of PC and emphasized the challenges for development of immunoprevention strategies.

Pancreatic ductal adenocarcinoma is one of the deadliest cancers worldwide and the fourth leading cause of cancer-related deaths in United States. Regardless of the advances in molecular pathogenesis and consequential efforts to suppress the disease, this cancer remains a major health problem in United States. By 2030, the projection is that pancreatic cancer will be climb up to be the second leading cause of cancer-related deaths in the United States. Pancreatic cancer is a rapidly invasive and highly metastatic cancer, and does not respond to standard therapies. Emerging evidence supports that the presence of a unique population of cells called cancer stem cells (CSCs) as potential cancer inducing cells and efforts are underway to develop therapeutic strategies targeting these cells. CSCs are rare quiescent cells, and with the capacity to self-renew through asymmetric/symmetric cell division, as well as differentiate into various lineages of cells in the cancer. Studies have been shown that CSCs are highly resistant to standard therapy and also responsible for drug resistance, cancer recurrence and metastasis. To overcome this problem, we need novel preventive agents that target these CSCs. Natural compounds or phytochemicals have ability to target these CSCs and their signaling pathways. Therefore, in the present review article, we summarize our current understanding of pancreatic CSCs and their signaling pathways, and the phytochemicals that target these cells including curcumin, resveratrol, tea polyphenol EGCG (epigallocatechin- 3-gallate), crocetinic acid, sulforaphane, genistein, indole-3-carbinol, vitamin E δ- tocotrienol, Plumbagin, quercetin, triptolide, Licofelene and Quinomycin. These natural compounds or phytochemicals, which inhibit cancer stem cells may prove to be promising agents for the prevention and treatment of pancreatic cancers.

Background and Objective: Current epidemiological studies report conflicting results for the effect of statin or metformin on pancreatic cancer overall survival. This literature review and meta-analysis summarize the studies reporting an association between statin or metformin use and overall survival of pancreatic cancer patients. Methods: We systematically searched for studies about the association between statin or metformin use and pancreatic cancer overall survival in electronic databases (PubMed, ISI Web of Science, MEDLINE, Cochrane, Scopus, Google Scholar). A meta-analysis based on hazard ratios (HRs) and 95% confidence intervals (CIs) was performed using random effect models. Heterogeneity between the studies was examined using I2 statistics, and sensitivity analyses were conducted to assess the robustness of the findings. Results: Of 116 statin-related articles identified, 6 retrospective cohort studies representing 12,057 patients were included. There was significant heterogeneity between studies. Statin use was associated with improved survival among pancreatic cancer patients (meta-HR = 0.75; 95% CI: 0.59, 0.90; P < 0.001). Of 311 metformin-related articles, 8 retrospective cohort studies and 2 randomized clinical trials, representing 3,042 patients were identified. Metformin use was associated with better overall survival among pancreatic cancer patients (meta-HR = 0.79; 95% CI: 0.70, 0.92, P < 0.001), and significant heterogeneity was observed between studies. Conclusion: Our findings suggest that the improved survival time of pancreatic cancer patients are associated with statin or metformin use. Due to the multiple sources of heterogeneity of the original studies, these findings should be considered cautiously, and confirmed with larger prospective individual-level studies.

Cancer is a major public health problem worldwide and is the second leading cause of death in the United States. Although cancer death rate has dropped by 23% since 1991, there are certain types of cancer for which death rates are still increasing, such as pancreatic cancer. There is an urgent need to find new therapies that could help improve this dreadful outcome. In this regard, the role of nutrition in health and disease has attracted much attention. Several dietary components are involved in metabolic, physiologic and cell signaling affecting tumor growth and progression. Although lipids, and more specifically polyunsaturated fatty acids, have been traditionally studied due to their health effects in cardiovascular disease, it is now clear that they can impact an extensive array of cellular processes that influence a wide range of diseases such as type II diabetes, inflammatory disorders and cancer. These biological activities may be grouped as regulation of: (1) membrane structure and function, (2) intracellular signaling pathways, (3) transcription factor activity, (4) gene expression, and (5) production of bioactive lipid mediators. The aim of this review is to assimilate the current state of knowledge about these potential mechanism(s) of action and signaling pathways modulated by polyunsaturated fatty acids in pancreatic cancer.