Role of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the resistance and toxicity of oxazaphosphorines

Abstract

Cyclophosphamide (CP) and ifosfamide (IF), represent an important group of therapeutic agents due to their substantial antitumor and immuno-modulating activity. Resistance to CP and IF is a major clinical problem often resulting in therapeutic failure. Overexpression of MRP4/ABCC4 conferred significant resistance to CP and IF in the 48-hr drug-exposure assays. The MRP4/ABCC4 inhibitors partially reversed the resistance observed with CP and IF. This resistance was enhanced by clofibrate (CFB) which is reported as MRP4 inducer in mice. In addition, CP significantly increased the MRP4 expression at both protein level and mRNA level in HEK293 cells at higher concentration, while IF significantly decreased the MRP4/ABCC4 expression at mRNA level at lower concentration only. The present study demonstrated that MRP4/ABCC4 play an important role in the resistance of CP and IF. It would be interesting to investigate the effect of the combination of CP or IF and MRP4 inhibitors on the cancer treatment.