Pharmacogenomic Analysis Identifies Increased Efficacy of Oxaliplatin in ABCB1 Overexpressing Tumors

Abstract

Oxaliplatin is a platinum-class drug used for advanced colorectal cancer, which is still incurable because of drug resistance. We applied a pharmacogenomic approach to correlate mRNA expression profiles of transporter genes and growth inhibitory potency of oxaliplatin in NCI-60. Expression of ABCB1 (MDR1, P-glycoprotein) gene positively correlated with anticancer activity of oxaliplatin, but not with cisplatin and other platinum analogs. This correlation suggests that cell lines with higher ABCB1 expression were more sensitive to oxaliplatin. MDR1 inhibitors cyclosporine A, PSC 833 or verapamil significantly reduced the sensitivity to oxaliplatin in ABCB1 overexpressing ovarian cancer cell line NCI/ADR-RES and colon cancer cell line HCT-15, whereas increased the sensitivity to MDR1 substrate drugs. These results provide evidence that the effect of oxaliplatin may be selective for tumor cells with high level of ABCB1 and overcome drug resistance. Such finding may provide an exciting prospect for future individualization of oxaliplatin-based cancer therapy