In Vitro and In Vivo Inhibition of MRP Gene Expression and Reversal of Multidrug Resistance by siRNA

Abstract

Clinical drug resistance to chemotherapeutic agents is one of the major hindrances in the treatment of human cancers. One mechanism by which a living cell can achieve multidrug resistance (MDR) is via the active efflux of a broad range of anti-cancer drugs through the cellular membrane by MDR proteins. Over-expression of multidrug resistance-associated protein 1 (MRP1) is one of the important MDR phenotypes. RNA interference (RNAi) is a fundamental cellular mechanism for silencing gene expression that can be harnessed for the development of new drugs. In our study, by using lipofectaminTM2000 (Invitrogen, Carlsbad, CA, USA) in vitro and electric pulse in vivo to delivery siRNA, we successfully inhibited MRP1 both at mRNA and protein level as determined by reverse transcription-PCR and western blot or immunohistochemistry. Furthermore, the efficacy of chemotherapeutic drugs (epirubicin) to tumour cells dramatically improved both in vivo and in vitro. These studies demonstrate that through efficient delivery siRNA, MRP1-mediated MDR can be reversed and siRNA can be used for further study in clinical cancer therapy. © 2010 The Authors. Basic & Clinical Pharmacology & Toxicology © 2010 Nordic Pharmacological Society.