Abstract 704: Upregulation of the human equilibrative nucleoside transporter 1 (hENT1) expression by indole-3-carbinol (I3C) in pancreatic cancer cell lines

Abstract

Abstract Pancreatic adenocarcinoma is the fourth most common cause of death in cancer in the Western world. In the past years, gemcitabine (GEM) has become the standard chemotherapeutic agent for patients with pancreatic cancer. However, a substantial number of patients fail to respond to therapy due to inherent or developed GEM chemoresistance. GEM is transported into cells mainly by the human equilibrative nucleoside transporter 1 (hENT1). Overexpression of hENT1 mRNA and protein in pancreatic carcinoma is known to correlate with better outcomes. In recent years, indole-3-carbinol (I3C), a dietary compound in cruciferous vegetables, has been shown to alter cancer cell survival by inducing apoptosis in vivo. I3C has also been shown to reverse multiple drug resistance by inhibiting efflux transporter, P-glycoprotein (P-gp) expression. In this study, the potential of I3C to modulate hENT1 expression and activity was evaluated in a panel of human pancreatic cancer cell lines, AsPC-1, BxPC-3, MiaPaca2, PANC-1 and PL-45. Our data showed that I3C at 50 and 100 uM significantly increased hENT1 mRNA and protein expression in BxPC-3 cell, MiaPaca2 cells and PANC-1 cells compared with the vehicle controls. In contrast, no such effect was observed in AsPC-1 and PL-45 cells with same treatment. The potential synergistic cytotoxic effect of I3C and GEM was also examined in all five pancreatic cancer cell lines. Pancreatic cancer cells were incubated with or without I3C at 50 uM for 24 h and then treated with GEM at different concentrations with or without I3C at 50 uM and a specific hENT1 inhibitor, NBMPR, at 50nM for 48 hours. MTS assay was used for cell viability measurement. Our data showed that I3C decreased IC50 by 6.8, 8.1 and 8.4 folds in PANC-1, MiaPaca2 and BxPC-3 cells respectively, and only 2.7 and 2.0 folds in AsPC-1 and PL-45 cells respectively, compared with GEM alone treated cells. Investigation also found that NBMPR, a specific inhibitor of hENT1, only abrogated a part of the augmented effect of I3C in response to GEM in all five pancreatic cell lines. The present study provides evidence that increasing hENT1 expression is a novel mechanism of the antitumor effect of I3C. The combination of GEM and I3C may be an effective strategy to overcome the GEM chemoresistance in pancreatic cancer patients. This affirms our hypothesis that I3C could be an adjuvant therapy improving the response to GEM treatment in patients with pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 704. doi:10.1158/1538-7445.AM2011-704