Inhibition of Cytochrome P450 and Multidrug Resistance Proteins Potentiates the Efficacy of All-Trans Retinoic Acid in Pancreatic Cancer In Vitro and In Vivo

Objectives: 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. We tested the hypothesis that blocking atRA degradation and elimination from the cell would potentiate its effectiveness in pancreatic cancer therapy.

Methods: In vitro, AsPc-1 and HPAF cells were co-treated with atRA and inhibitors of either multidrug resistance (MDR: verapamil, LY335979, and quinidine) or cytochrome P450 (CYP450s: troleandomycin, clotrimazole and liarozole). In addition, cells were co treated with atRA and antisense oligonucleotides against MRP, Pgp, CYP26 and CYP3A4. Proliferation and apoptosis were investigated. In vivo, AsPc-1 xenografts were treated with atRA, verapamil, and troleandomycin alone or in combination.

Results: The anti-proliferative effect of atRA on AsPc-1 and HPAF cells was markedly potentiated by the inhibition of MDR and CYP450 or by antisense oligonucleotides to reduce their production. The combination also enhanced atRA-induced apoptosis. Coadministration of inhibitors of MDR and CYP450 also potentiated the inhibitory effect of atRA on growth of xenografts.

Conclusions: Co-treatment of pancreatic cancer with low nontoxic doses of atRA combined with MDR blockade and inhibition of CYP450 is effective suppressing tumor growth, suggesting a novel clinical application.