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Pancreatic cancer remains one of the most devastating diseases in terms of patient mortality rates for which current treatment options are very limited. 3,4-Difluorobenzylidene curcumin (CDF) is a nontoxic analog of curcumin (CMN) developed in our laboratory, which exhibits extended circulation half-life, while maintaining high anticancer activity and improved pancreas specific accumulation in vivo , compared with CMN. CDF however has poor aqueous solubility and its dose escalation for systemic administration remains challenging. We have engineered self-assembling nano-micelles of amphiphilic styrene-maleic acid copolymer (SMA) with CDF by non-covalent hydrophobic interactions. The SMA-CDF nano-micelles were characterized for size, charge, drug loading, release, serum stability, and in vitro anticancer activity. The SMA-CDF nano-micelles exhibited tunable CDF loading from 5 to 15% with excellent aqueous solubility, stability, favorable hemocompatibility and sustained drug release characteristics. The outcome of cytotoxicity testing of SMA-CDF nano-micelles on MiaPaCa-2 and AsPC-1 pancreatic cancer cell lines revealed pronounced antitumor response due to efficient intracellular trafficking of the drug loaded nano-micelles. Additionally, the nano-micelles are administrable via the systemic route for future in vivo studies and clinical translation. The currently developed SMA based nano-micelles thus portend to be a versatile carrier for dose escalation and targeted delivery of CDF, with enhanced therapeutic margin and safety. [ABSTRACT FROM AUTHOR]

Abstract: Thymoquinone (TQ), isolated from the seeds of Nigella sativa, show moderate efficacy against pancreatic cancer. In the present work we report synthesis and characterization of novel TQ analogs appended with gallate and fluorogallate pharmacophores and evaluation of their effects against pancreatic cancer cell lines for cell viability and induction of apoptosis. The efficacy of the analogs alone or in combination with Gemcitabine was assessed in vitro. LC–MS spectra of ATQTHB and ATQTFB showed major peaks corresponding to expected M+1 fragment at 316.34 and 322.34 respectively. Molecular docking studies revealed good fit for these analogs in the COX-2 protein cavity with better binding energies compared to parent TQ compound. Present TQ analogs exhibit superior anti-proliferative activity, excellent chemo-sensitizing activity against pancreatic cancer in vitro and in combination with Gemcitabine. [Copyright &y& Elsevier]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most frequently diagnosed cancers and the fourth leading cause of cancer-related death in the United States, suggesting that there is an urgent need to design novel strategies for achieving better treatment outcome of patients diagnosed with PDAC. Our previous study has shown that activation of Notch and NF-κB play a critical role in the development of PDAC in the compound K-RasG12D and Ink4a/Arf deficient transgenic mice. However, the exact molecular mechanism by which mutated K-Ras and Ink4a/Arf deficiency contribute to progression of PDAC remains largely elusive. In the present study, we used multiple methods, such as real-time RT-PCR, Western blotting assay, and immunohistochemistry to gain further mechanistic insight. We found that the deletion of Ink4a/Arf in K-RasG12D expressing mice led to high expression of PDGF-D signaling pathway in the tumor and tumor-derived cell line (RInk-1 cells). Furthermore, PDGF-D knock-down in RInk-1 cells resulted in the inhibition of pancreatosphere formation and down-regulation of EZH2, CD44, EpCAM, and vimentin. Moreover, we demonstrated that epithelial-mesenchymal transition (EMT) was induced in the compound mice, which is linked with aggressiveness of PDAC. In addition, we demonstrated that tumors from compound transgenic mice have higher expression of cancer stem cell (CSC) markers. These results suggest that the acquisition of EMT phenotype and induction of CSC characteristics could be linked with the aggressiveness of PDAC mediated in part through the activation of PDGF-D, signaling. J. Cell. Physiol. 228: 556-562, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Hypoxia is known to play critical roles in cell survival, angiogenesis, tumor invasion, and metastasis. Hypoxia mediated over-expression of hypoxia-inducible factor (HIF) has been shown to be associated with therapeutic resistance, and contributes to poor prognosis of cancer patients. Emerging evidence suggest that hypoxia and HIF pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and also maintains the vicious cycle of inflammation-all which lead to therapeutic resistance. However, the precise molecular mechanism(s) by which hypoxia/HIF drives these events are not fully understood. Here, we show, for the first time, that hypoxia leads to increased expression of VEGF, IL-6, and CSC signature genes Nanog, Oct4 and EZH2 consistent with increased cell migration/invasion and angiogenesis, and the formation of pancreatospheres, concomitant with increased expression of miR-21 and miR-210 in human pancreatic cancer (PC) cells. The treatment of PC cells with CDF, a novel synthetic compound inhibited the production of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 and miR-210 under hypoxia. CDF also led to decreased cell migration/invasion, angiogenesis, and formation of pancreatospheres under hypoxia. Moreover, CDF decreased gene expression of miR-21, miR-210, IL-6, HIF-1α, VEGF, and CSC signatures in vivo in a mouse orthotopic model of human PC. Collectively, these results suggest that the antitumor activity of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become a novel, and effective anti-tumor agent for PC therapy. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a deadly disease and has the worst prognosis among almost all cancers and is in dire need of new and improved therapeutic strategies. Conditioning of tumor cells with chemotherapeutic drug has been shown to enhance the anti-tumor effects of cancer vaccines and adoptive cell therapy. In this study, we investigated the immunomodulatory effects of pan-Bcl-2 inhibitor AT-101 on pancreatic cancer (PC) cell cytotoxicity by activated T cells (ATC). The effects of AT- 101 on cytotoxicity, early apoptosis, and Granzyme B (GrzB) and IFN-γ signaling pathways were evaluated during EGFR bispecific antibody armed ATC (aATC)-mediated killing of L3.6pl and MiaPaCa-2 PC cells pre-sensitized with AT-101. We found that pretreatment of tumor cells with AT-101 enhanced susceptibility of L3.6pl and MiaPaCa-2 tumor cells to ATC and aATC-mediated cytotoxicity, which was in part mediated via enhanced release of cytolytic granule GrzB from ATC and aATC. AT-101-sensitized L3.6pl cells showed up-regulation of IFN-γ-mediated induction in the phosphorylation of Ser 727 -Stat1 (pS727 -Stat1), and IFN-γ induced dephosphorylation of phospho-Tyr 705 -Stat3 (pY705 -Stat3). Priming (conditioning) of PC cells with AT-101 can significantly enhance the anti-tumor activity of EGFRBi armed ATC through increased IFN-γ induced activation of pS727 -Stat1 and inhibition of pY705 -Stat3 phosphorylation, and resulting in increased ratio of pro-apoptotic to anti-apoptotic proteins. Our results verify enhanced cytotoxicity after a novel chemotherapy conditioning strategy against PC that warrants further in vivo and clinical investigations. [ABSTRACT FROM AUTHOR]

Human pancreatic cancer (PC) is an aggressive disease, which has been recapitulated in transgenic animal model that provides unique opportunity for mechanistic understanding of disease progression and also for testing the efficacy of novel therapeutics. Emerging evidence suggests deregulated expression of microRNAs (miRNAs) in human PC, and thus we investigated the expression of miRNAs in pancreas tissues obtained from transgenic mouse models of K-Ras (K), Pdx1-Cre (C), K-Ras;Pdx1-Cre (KC), and K-Ras;Pdx1-Cre;INK4a/Arf (KCI), initially from pooled RNA samples using miRNA profiling, and further confirmed in individual specimens by quantitative RT-PCR. We found over-expression of miR-21, miR-221, miR-27a, miR-27b, and miR-155, and down-regulation of miR-216a, miR-216b, miR-217, and miR-146a expression in tumors derived from KC and KCI mouse model, which was consistent with data from KCI-derived RInk-1 cells. Mechanistic investigations revealed a significant induction of EGFR, K-Ras, and MT1-MMP protein expression in tissues from both KC and KCI mouse compared to tissues from K or C, and these results were consistent with similar findings in RInk-1 cells compared to human MIAPaCa-2 cells. Furthermore, miR-155 knock-down in RInk-1 cells resulted in the inhibition of cell growth and colony formation consistent with down-regulation of EGFR, MT1-MMP, and K-Ras expression. In addition, miR-216b which target Ras, and forced re-expression of miR-216b in RInk-1 cells showed inhibition of cell proliferation and colony formation, which was correlated with reduced expression of Ras, EGFR, and MT1-MMP. These findings suggest that these models would be useful for preclinical evaluation of novel miRNA-targeted agents for designing personalized therapy for PC. J. Cell. Physiol. 227: 3373-3380, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Many critical factors such as hypoxia, nutrient deficiency, activation of glycolytic pathway/Warburg effect contribute to the observed low pH in tumors compared to normal tissue. Studies suggest that such tumor specific acidic environment can be exploited for the development of therapeutic strategies against cancer. Independent observations show reduction in pH of mammalian cells undergoing internucleosomal DNA fragmentation and apoptosis. As such, our group has extensively demonstrated that anticancer mechanisms of different plant polyphenols involve mobilization of endogenous copper and consequent internucleosomal DNA breakage. Copper is redox active metal, an essential component of chromatin and is sensitive to subtle pH changes in its microenvironment. Here we explored whether, acidic pH promotes growth inhibition, apoptosis, and DNA damaging capacity of chemopreventive agent resveratrol. Our results reveal that growth inhibition and internucleosomal DNA fragmentation induced apoptosis in Capan-2 and Panc-28 pancreatic cancer cell lines (and not in normal HPDE cells) by resveratrol is enhanced at lower pH. Using comet assay, we further demonstrate that DNA breakage by resveratrol is enhanced with acidification. Membrane permeable copper specific chelator neocuproine (and not iron chelator orthophenanthroline) abrogated growth inhibition and apoptosis by resveratrol. Western blot results show enhanced activation of DNA laddering marker H2.aX by resveratrol at acidic pH that was reversed by neocuproine and not by orthophenanthroline. Our findings provide irrevocable proof that low pH environment can be turned into tumor weakness and assist in eradication of cancer cells by resveratrol. J. Cell. Physiol. 227: 1493-1500, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains the fourth most common cause of cancer-related death in the United States. Therefore, novel strategies for the prevention and/or treatment are urgently needed. Genistein has been found to be responsible for lowering the rate of pancreatic cancer. However, the molecular mechanisms by which genistein elicits its effects on pancreatic cancer cells has not been fully elucidated. Therefore, the purpose of the current study was to elucidate the anti-cancer mechanism(s) of genistein. Multiple molecular techniques, such as Real-time RT-PCR, Western blot analysis, invasion assay, immunofluorescence assay, gene transfection, MTT assay, and Histone/DNA ELISA, were used. We found that genistein inhibited cell growth accompanied by induction of apoptosis with concomitant attenuation of FoxM1 and its downstream genes, such as survivin, cdc25a, MMP-9, and VEGF, resulting in the inhibition of pancreatic cancer cell invasion. We also found that down-regulation of FoxM1 by siRNA prior to genistein treatment resulted in enhanced cell growth inhibition and induction of apoptosis. This is the first report showing the molecular role of FoxM1 in mediating the biological effects of genistein in pancreatic cancer cells, suggesting that FoxM1 could be a novel target for the treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Abstract: Pancreatic cancer is the fourth leading cause of cancer death in the United States with a very low survival rate of 5 years. To better design new preventive and/or therapeutic strategies for the fight against pancreatic cancer, the knowledge of the pathogenesis of pancreatic cancer at the molecular level is very important. It has been known that the development and the progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways among which the EGFR, Akt, and NF-κB pathways appear to be most relevant. Therefore, the strategies targeting EGFR, Akt, NF-κB, and their downstream signaling could be promising for the prevention and/or treatment of pancreatic cancer. In this brief review, we will summarize the current knowledge regarding the pathogenesis, prevention, and treatment of pancreatic cancer. [Copyright &y& Elsevier]

The current study was aimed to develop a targeted dendrimer formulation of 3, 4-difluorobenzylidene curcumin (CDF) and evaluate its potential in CD44 targeted therapy for pancreatic cancer. Using amine terminated fourth generation poly(amidoamine) (PAMAM) dendrimer nanocarrier and hyaluronic acid (HA) as a targeting ligand, we engineered a CD44-targeted PAMAM dendrimer (HA-PAMAM) formulation of CDF. The resulting dendrimer nanosystem (HA-PAMAM-CDF) had a particle size and surface charge of 9.3 ± 1.5 nm and −7.02 ± 9.53 mV, respectively. When CD44 receptor overexpressing MiaPaCa-2 and AsPC-1 human pancreatic cancer cells were treated with HA-PAMAM-CDF, a dose-dependent cytotoxicity was observed. Furthermore, blocking the CD44 receptors present on the MiaPaCa-2 cells using free excess soluble HA prior to treatment with HA-PAMAM-CDF nano-formulation resulted in 1.71 fold increase in the IC 50 value compared to non-targeted formulation (PAMAM-CDF), confirming target specificity of HA-PAMAM-CDF. Additionally, HA-PAMAM-CDF formulation when compared to PAMAM-CDF, displayed higher cellular uptake in MiaPaCa-2 cancer cell lines as shown by fluorescence studies. In summary, the novel CD44 targeted dendrimer based nanocarriers appear to be proficient in mediating site-specific delivery of CDF via CD44 receptors, with an improved therapeutic margin and safety. [ABSTRACT FROM AUTHOR]

The histone methyl transferase EZH2 is a central epigenetic regulator of cell survival, proliferation, and cancer stem cell (CSC) function. EZH2 expression is increased in various human cancers, including highly aggressive pancreatic cancers, but the mechanisms underlying for its biologic effects are not yet well understood. In this study, we probed EZH2 function in pancreatic cancer using diflourinated-curcumin (CDF), a novel analogue of the turmeric spice component curcumin that has antioxidant properties. CDF decreased pancreatic cancer cell survival, clonogenicity, formation of pancreatospheres, invasive cell migration, and CSC function in human pancreatic cancer cells. These effects were associated with decreased expression of EZH2 and increased expression of a panel of tumor-suppressive microRNAs (miRNA), including let-7a,b,c,d, miR-26a, miR-101, miR-146a, and miR-200b,c that are typically lost in pancreatic cancer. Mechanistic investigations revealed that reexpression of miR-101 was sufficient to limit the expression of EZH2 and the proinvasive cell surface adhesion molecule EpCAM. In an orthotopic xenograft model of human pancreatic cancer, administration of CDF inhibited tumor growth in a manner associated with reduced expression of EZH2, Notch-1, CD44, EpCAM, and Nanog and increased expression of let-7, miR-26a, and miR-101. Taken together, our results indicated that CDF inhibited pancreatic cancer tumor growth and aggressiveness by targeting an EZH2-miRNA regulatory circuit for epigenetically controlled gene expression. Cancer Res; 72(1); 335--45. ©2011 AACR. [ABSTRACT FROM AUTHOR]

Small molecule inhibitors (SMIs) of murine double minute 2 (MDM2) are known to restore the apoptotic and cell cycle regulatory functions of p53 by disrupting the MDM2–p53 interaction. In principle, these SMIs are not effective against tumours with mutation in the tumour suppressor p53 (mut-p53), which is known to be present in approximately 50% of all cancers. In this study we are reporting, for the first time, that MI-319 in combination with cisplatin induced cell growth inhibition and apoptosis in pancreatic cancer (PC) cells irrespective of their p53 mutational status. MI-319–cisplatin combination synergistically suppressed cell growth (MTT Combination Index [CI]<1) and colony formation (clonogenic assay) and induced apoptosis. Western blot analysis and siRNA silencing studies in mutant as well as p53 null cells highlighted a mechanism involving p73 which is also known to be under the regulation of MDM2, and unlike p53, it is rarely mutated in PC. Down-regulating MDM2 using siRNA enhanced p73 reactivation and increased cell death. Further, the combination effectively reduced tumour growth in both wt-p53 and mut-p53 tumour xenograft models (50% Capan-2 animals were tumour free). Consistent with our in vitro results, remnant tumour tissue analysis showed up-regulation of p73 and the cell cycle regulator p21. In conclusion, this study highlights a new role of MDM2 inhibitors in combination with cisplatin, and thus warrants further clinical investigation in human pancreatic tumours containing both wt-p53 and mut-p53. [Copyright &y& Elsevier]

Abstract: Pancreatic cancer (PC) remains the fourth most common cause of cancer related death in the United States. Therefore, novel strategies for the prevention and treatment are urgently needed. Numerous dietary and pharmacological agents have been proposed as alternative strategies for the prevention and/or treatment of PC. Isoflavone is a prominent flavonoid found in soy products and has been proposed to be responsible for lowering the incidence of PC in Asians. Similarly, curcumin, an active ingredient of turmeric, that inhibits growth of malignant neoplasms, has a promising role in the prevention and/or treatment of PC. Here we examined whether isoflavone together with curcumin could elicit a greater inhibition of growth of PC cells than either agent alone, and also sought to determine the molecular mechanism of action. We found that the inhibition of cell growth and induction of apoptosis was significantly greater in the combination group than that could be achieved by either agent alone. These changes were associated with decreased Notch-1 expression and DNA binding activity of NF-κB and its target genes such as Cyclin D1, Bcl-2, and Bcl-xL. Moreover, we found that the combination of four natural agents at lower concentration was much more effective. Collectively, our results suggest that diet containing multiple natural products should be preferable over single agents for the prevention and/or treatment of PC. The superior effects of the combinatorial treatment could partly be attributed to the inhibition of constitutive activation of Notch-1 and NF-κB signaling pathways. [Copyright &y& Elsevier]

Aberrant expression of microRNAs (miRNAs) plays important roles in the development and progression of pancreatic cancer (PC). Expression analysis of miR-146a in human PC tissues showed decreased expression in about 80% of samples compared to corresponding non-cancerous tissue. Moreover, expression of miR-146a in eight PC cell lines, and in pancreatic tissues obtained from transgenic mouse models of K-Ras (K), Pdx1-Cre (C), K-Ras;Pdx1-Cre (KC) and K-Ras;Pdx1-Cre;INK4a/Arf (KCI), showed down-regulation of miR-146a expression in KCI mice which was in part led to over-expression of its target gene, epidermal growth factor receptor (EGFR). Treatment of PC cells with CDF, a novel synthetic compound, led to re-expression of miR-146a, resulting in the down-regulation of EGFR expression. Moreover, re-expression of miR-146a by stable transfection or treatment with CDF in vivo (xenograft animal model) resulted in decreased tumor growth which was consistent with reduced EGFR, ERK1, ERK2, and K-Ras expression. Further knock-down of miR-146a in AsPC-1 cells led to the up-regulation of EGFR expression and showed increased clonogenic growth. In addition, knock-down of EGFR by EGFR siRNA transfection of parental AsPC-1 cells and AsPC-1 cells stably transfected with pre-miR-146a resulted in decreased invasive capacity, which was further confirmed by reduced luciferase activity in cells transfected with pMIR-Luc reporter vector containing miR-146a binding site. Collectively, these results suggest that the loss of expression of miR-146a is a fundamental mechanism for over-expression of EGFR signaling and that re-expression of miR-146a by CDF treatment could be useful in designing personalized strategy for the treatment of human PC. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is one of the most deadly cancers. The higher mortality is in part due to treatment resistance and early onset of metastasis. The existence of cancer-stem-like cells (CSLCs) has been widely accepted to be responsible for tumor aggressiveness in PC. Emerging evidence suggests that CSLCs have the capacity for increased cell growth, cell migration/invasion, metastasis, and treatment resistance, which leads to poor clinical outcome. However, the molecular role of CSLCs in tumor development and progression is poorly understood. Therefore, mechanistic understanding, and targeted killing of CSLCs may provide a newer therapeutic strategy for the treatment of PC. It has been well accepted that microRNAs (miRNAs) play critical roles during tumor development and progression through deregulation of multiple genes. Moreover, deregulated expression of miRNAs may also play a key role in the regulation of CSLC characteristics and functions. Here we show that isolated CD44+/CD133+/EpCAM+ cells (triple-marker-positive cells) from human PC cell lines, MiaPaCa-2 and L3.6pl cells, display aggressive characteristics, such as increased cell growth, clonogenicity, cell migration, and self-renewal capacity, which is consistent with overexpression of CSLC signatures/markers. We also found deregulated expression of over 400 miRNAs, including let-7, miR-30, miR-125b, and miR-335, in CSLCs. As a proof-of-concept, knockdown of miR-125b resulted in the inhibition of tumor cell aggressiveness of CSLCs (triple-marker-positive cells), consistent with the downregulation of CD44, EpCAM, EZH2, and snail. These results clearly suggest the importance of miRNAs in the regulation of CSLC characteristics, and may serve as novel targets for therapy. [ABSTRACT FROM AUTHOR]

Subpopulations of cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) have been identified from most tumors, including pancreatic cancer (PC), and the existence of these cells is clinically relevant. Emerging evidence suggests that CSLCs participate in cell growth/proliferation, migration/invasion, metastasis, and chemo-radiotherapy resistance, ultimately contributing to poor clinical outcome. However, the pathogenesis and biological significance of CSLCs in PC has not been well characterized. In the present study, we found that isolated triple-marker-positive (CD44+/CD133+/EpCAM+) cells of human PC MiaPaCa-2 and L3.6pl cells behave as CSLCs. These CSLCs exhibit aggressive behavior, such as increased cell growth, migration, clonogenicity, and self-renewal capacity. The mRNA expression profiling analysis showed that CSLCs (CD44+/CD133+/EpCAM+) exhibit differential expression of more than 1,600 mRNAs, including FoxQ1, compared with the triple-marker-negative (CD44-/CD133-/EpCAM-) cells. The knockdown of FoxQ1 by its siRNA in CSLCs resulted in the inhibition of aggressive behavior, consistent with the inhibition of EpCAM and Snail expression. Mouse xenograft tumor studies showed that CSLCs have a 100-fold higher potential for tumor formation and rapid tumor growth, consistent with over-expression of CSC-associated markers/mediators, including FoxQ1, compared with its parental MiaPaCa-2 cells. The inhibition of FoxQ1 attenuated tumor formation and growth, and expression of CSC markers in the xenograft tumor derived from CSLCs of MiaPaCa-2 cells. These data clearly suggest the role of differentially expressed genes in the regulation of CSLC characteristics, further suggesting that targeting some of these genes could be important for the development of novel therapies for achieving better treatment outcome of PC. [ABSTRACT FROM AUTHOR]

Abstract: Activation of Notch-1 is known to be associated with the development and progression of human malignancies including pancreatic cancer. Emerging evidence suggest that the acquisition of epithelial–mesenchymal transition (EMT) phenotype and induction of cancer stem cell (CSC) or cancer stem-like cell phenotype are interrelated and contributes to tumor recurrence and drug resistance. The molecular mechanism(s) by which Notch-1 contributes to the acquisition of EMT phenotype and CSC self-renewal capacity has not been fully elucidated. Here we show that forced over-expression of Notch-1 leads to increased cell growth, clonogenicity, migration and invasion of AsPC-1 cells. Moreover, over-expression of Notch-1 led to the induction of EMT phenotype by activation of mesenchymal cell markers such as ZEB1, CD44, EpCAM, and Hes-1. Here we also report, for the first time, that over-expression of Notch-1 leads to increased expression of miR-21, and decreased expression of miR-200b, miR-200c, let-7a, let-7b, and let-7c. Re-expression of miR-200b led to decreased expression of ZEB1, and vimentin, and increased expression of E-cadherin. Over-expression of Notch-1 also increased the formation of pancreatospheres consistent with expression of CSC surface markers CD44 and EpCAM. Finally, we found that genistein, a known natural anti-tumor agent inhibited cell growth, clonogenicity, migration, invasion, EMT phenotype, formation of pancreatospheres and expression of CD44 and EpCAM. These results suggest that the activation of Notch-1 signaling contributes to the acquisition of EMT phenotype, which is in part mediated through the regulation of miR-200b and CSC self-renewal capacity, and these processes could be attenuated by genistein treatment. [Copyright &y& Elsevier]

Abstract: Pancreatic cancer (PC) is one of the most lethal malignant diseases with the worst prognosis. It is ranked as the fourth leading cause of cancer-related deaths in the United States. Many risk factors have been associated with PC. Interestingly, large numbers of epidemiological studies suggest that obesity and diabetes, especially type-2 diabetes, are positively associated with increased risk of PC. Similarly, these chronic diseases (obesity, diabetes, and cancer) are also a major public health concern. In the U.S. population, 50 percent are overweight, 30 percent are medically obese, and 10 percent have diabetes mellitus (DM). Therefore, obesity and DM have been considered as potential risk factors for cancers; however, the focus of this article is restricted to PC. Although the mechanisms responsible for the development of these chronic diseases leading to the development of PC are not fully understood, the biological importance of the activation of insulin, insulin like growth factor-1 (IGF-1) and its receptor (IGF-1R) signaling pathways in insulin resistance mechanism and subsequent induction of compensatory hyperinsulinemia has been proposed. Therefore, targeting insulin/IGF-1 signaling with anti-diabetic drugs for lowering blood insulin levels and reversal of insulin resistance could be useful strategy for the prevention and/or treatment of PC. A large number of studies have demonstrated that the administration of anti-diabetic drugs such as metformin and thiazolidinediones (TZD) class of PPAR-γ agonists decreases the risk of cancers, suggesting that these agents might be useful anti-tumor agents for the treatment of PC. In this review article, we will discuss the potential roles of metformin and TZD anti-diabetic drugs as anti-tumor agents in the context of PC and will further discuss the complexities and the possible roles of microRNAs (miRNAs) in the pathogenesis of obesity, diabetes, and PC. [Copyright &y& Elsevier]