Abstract 4436: Metformin upregulates hENT1 expression and enhances gemcitabine efficacy in pancreatic cancer cells

Abstract

Abstract Pancreatic cancer is the 4th leading cause of cancer death and is normally diagnosed at a late stage due to the lack of symptoms and early detection. Pancreatic cancer patients have one of the worst prognoses among all cancer types with a 5 year survival rate of less than 5%. Despite significant improvement in understanding molecular and epigenetic changes of this disease, the prognosis and management remained unchanged. The golden standard of advanced pancreatic cancer treatment is gemcitabine or gemcitabine with more targeted therapy. Patients treated with gemcitabine can, however, eventually develop resistance to this drug. Previously published data from our laboratory demonstrated enhanced efficacy of gemcitabine with the dietary agent, indole-3-carbinol (I3C) though up-regulation of the human equilibrative nucleoside transporter (hENT1). hENT1 is the major drug transporter for gemcitabine. One of the drugs currently being investigated for treatment of pancreatic cancer is metformin. Metformin is one of the most widely prescribed drugs for the treatment of type 2 diabetes mellitus. Metformin has exhibited both chemopreventive and chemotherapeutic activities in preclinical human pancreatic cancer cells and animal models. Currently this drug is in clinical trial for pancreatic cancer. Metformin has been found to be transported by a member of the equilibrative nucleoside transporter (ENT) family named ENT4.The current study examined the potential efficacy and regulation of hENT1 in pancreatic cancer cells when treated with gemcitabine and/or metformin. Several pancreatic cell lines (Mia PaCa-2, AsPC-1, Su86.86 and PANC-1) were examined for modulation of hENT1 expression when treated with gemcitabine or metformin or in combination for 24h and 72h. The results varied for each of the cell lines. After 24 h treatment, hENT1 expression analysis of Su86.86 and PANC-1 gemcitabine resistant cell lines showed no change in hENT1 expression levels. After 72h of treatment with gemcitabine and/or metformin hENT1 expression was up-regulated (p<0.05); however, metformin did not enhance the efficacy of gemcitabine. In AsPC-1, a cell line with moderate gemcitabine resistance, hENT1 expression was down-regulated (p<0.05) after 24 h treatment with gemcitabine and/or metformin; however, after 72h of treatment with gemcitabine and metformin, metformin increase the efficacy of gemcitabine (p<0.05). In MIA Paca-2, a gemcitabine sensitive cell line, the expression of hENT1 was up-regulated (p<0.05) after 24h treatment with gemcitabine. Metformin and combination with gemcitabine treatments also upregulated the expression of hENT1 (p<0.05) but metformin did not increase the efficacy of gemcitabine. There was no change in expression for MIA Paca-2 cells treated for 72h. Based on initial studies, the sensitivity of pancreatic cancer cell lines to gemcitabine/metformin combination is through up-regulation of hENT1. Citation Format: Stancy J. Joseph, Taylor Osborne, Beverly Word, Beverly Lyn-Cook. Metformin upregulates hENT1 expression and enhances gemcitabine efficacy in pancreatic cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4436. doi:10.1158/1538-7445.AM2015-4436