In vivo reversal of p-glycoprotein-mediated multidrug resistance by efficient delivery of Stealth™ RNAi

Abstract

P-Glycoprotein-mediated multidrug resistance (MDR) is a major hurdle in cancer therapy. P-Glycoprotein is a 170 KD protein encoded by the MDR1 gene. Over-expression of P-glycoprotein is considered one of the characteristics of the MDR phenotype, thus down-regulation of the MDR1 gene expression will circumvent MDR partly. RNA interference (RNAi) is a process that can result in sequence-specific gene silencing by cleavage target mRNA. Electroporation has been demonstrated to be a promising and efficient method for gene delivery and has been successfully applied in gene therapy. In our study, by using electric pulse to delivery Stealth™ RNAi into nude mice NCI-H460 tumour xenografts, we successfully inhibited MDR1 both at the mRNA level as determined by reverse transcription-polymerase chain reaction and at the protein level as determined by immunohistochemistry. Furthermore, by administration of navelbine after transfection with Stealth™ RNAi targeted on the MDR1 gene, its depression to tumour xenografts dramatically improved by nine times. These studies demonstrate that through electrotransfection of Stealth™ RNAi, P-glycoprotein-mediated MDR can be reversed. © 2008 The Authors.