In vitro transport ability of ABCC2 (G1249A) polymorphic variant towards anticancer drugs

Abstract

Objective: Multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2 gene, is involved in the efflux of certain anticancer drugs. Here we observed whether the ABCC2 (G1249A) polymorphism impacts the transport abilities of MRP2-dependent paclitaxel, docetaxel, and doxorubicin in recombinant LLC-PK1 cell lines. Methods: LLC-PK1 cell lines transfected with ABCC21249G wild-type and ABCC21249A variant alleles were used to evaluate the sensitivity, intracellular accumulation, and trans-membrane transport of paclitaxel, docetaxel, and doxorubicin. Results: The recombinant ABCC21249A variant cell line showed higher IC50 values for paclitaxel and doxorubicin than ABCC21249G wild-type cell system (p<0.01). Intracellular accumulations of paclitaxel and doxorubicin in cells transfected with ABCC21249A variant allele were significantly decreased compared to cells transfected with ABCC21249G wild-type allele (p<0.01). The efflux ratios of paclitaxel and doxorubicin across ABCC21249A cell line were significantly increased compared with ABCC21249G cell system (p<0.01). However, ABCC2 (G1249A) polymorphism had no effect on the transport activity of MRP2-mediated docetaxel. Conclusion: Our results indicate that ABCC2 (G1249A) polymorphism affects the transport activities of MRP2-dependent paclitaxel and doxorubicin, resulting in greater efflux of these anticancer drugs.