Retinoic acid enhances the cytotoxic effects of gemcitabine and cisplatin in pancreatic adenocarcinoma cells

Introduction: Retinoids, which are derivatives of vitamin A, are important factors involved in the control of biologic functions such as cell growth a nd differentiation, development, and carcinogenesis. We have shown previous ly that the naturally occurring retinoids all-trans-retinoic acid (ATRA) an d 9-cis-retinoic acid (9cRA) induce growth inhibition followed by apoptosis in pancreatic adenocarcinoma cells in vitro. Aim: To evaluate the efficacy of retinoids in combination with the chemothe rapeutic drugs gemcitabine and cisplatin. Methodology: In vitro growth inhibition and induction of apoptosis by diffe rent combinations of retinoids and cytotoxic drugs were studied by using th e T3M-4 and BxPc-3 cell lines. For in vivo studies, T3M-4 cells were inject ed subcutaneously in nude mice. Results: Pre-treatment of pancreatic adenocarcinoma cells with ATRA or 9cRA before the addition of the drugs resulted in significant reduction in cell number compared with treatment with the drugs alone. Pre-treatment with 9c RA followed by gemcitabine or cisplatin alone also resulted in a strong inc rease in the percentage of cells undergoing programmed cell death, or apopt osis. Furthermore, there was an indication that the combination of ATRA and gemcitabine caused increased apoptosis in vivo. Conclusion: Our results clearly suggest the need for additional studies exp loring the potential role of the combination of retinoids and gemcitabine i n the management of pancreatic cancer.