In Vitro and in Vivo Studies on the Antitumor Efficacy of All-Trans Retinoic Acid Combination with Inhibitors of Cytochrome P450 and Multidrug Resistance Proteins in Pancreatic Carcinoma

All-trans retinoic acid (atRA) potently induces differentiation and apoptosis in pancreatic cancer. However, the clinical use of retinoids is limited by retinoid resistance or development of toxicity at high doses. In vitro, we studied the effect of combining atRA with pharmacological inhibitors of either multidrug resistance (MDR): verapamil, and LY335979 or cytochrome P450 (CYP450s): troleandomycin, and liarozole on atRA potency in pancreatic cancer therapy. Our results showed that the combined treatment of atRA with either of the two drugs exerted stronger inhibition on AsPC-1 proliferation, when compared to the treatment with either drug alone. The combination also enhanced atRA-induced cell death. In vivo, nude mice with AsPc-1 xenografts were treated with atRA, verapamil, and troleandomycin alone or in combination. Co-administration of inhibitors of MDR and CYP450 also potentiated the inhibitory effect of atRA on growth of xenografts that was associated with decreased protein levels of pAKT and pERK. We conclude that Co-treatment of pancreatic cancer with low non-toxic doses of atRA combined with MDR blockade and inhibition of CYP450 is effective in suppressing tumor growth, suggesting a novel clinical application. Key words: retinoic acid, verapamil, troleandomycin, proliferation, apoptosis, pancreatic cancer