Reversal of MDR1/P-glycoprotein-mediated multidrug resistance by RNA interference

Simultaneous resistance of cancer cells to multiple cytotoxic drugs, multidrug resistance (MDR), is the major limitation to the successful chemotherapeutic treatment of disseminated neoplasms. The "classical" MDR phenotype results from decreased drug accumulation mediated by the adenosine triphosphate binding cassette (ABC)-transporter P-glycoprotein (MDR1/P-gp, ABCB1), the product of the human MDR1 gene. Inhibition of the drug extrusion activity of MDR1/P-gp by low-molecular weight pharmacologically active compounds as a method to reverse MDR in cancer patients has been studied extensively, but the clinical results have generally been disappointing. Thus, experimental therapeutic strategies to overcome MDR were developed. These strategies included gene therapeutic approaches with antisense oligonucleotides (ODNs) or ribozymes, and, most recently, the application of the RNA interference (RNAi) technology. RNAi is a physiological double stranded RNA-triggered mechanism resulting in gene-silencing in a sequence-specific manner. Transient RNAi can be attained by application of small interfering RNAs (siRNAs), whereas a stable RNAi-mediated gene-silencing can be achieved by transfection of mammalian cells with short hairpin RNA (shRNA) encoding expression vectors. Both techniques were applied to overcome MDR1/P-gp-mediated MDR in different in vitro models. In this mini review, the utilization of RNAi technology as a potential gene therapeutic tool for reversal of MDR will be discussed. (c) 2005 Elsevier B.V. All rights reserved.