Comparative study on ABCB1-dependent efflux of anthracyclines and their metabolites: consequences for cancer resistance

Abstract

Abstract Purpose ABC transporters are transmembrane proteins involved in ATP-dependent translocation of organic compounds across cellular membranes. Among them, ABCB1 (P-glycoprotein, MDR1) transporter is one of the most important involved in cancer multi-drug resistance. It also plays a significant role in cancer resistance against anthracyclines, an anticancer group of drugs, including doxorubicin and daunorubicin. Carbonyl reductases and aldo-keto reductases metabolize anthracyclines to carbonyl-reduced, hydroxy metabolites, which have impaired cytotoxic properties. However, metabolites efflux by ABCB1 transporter is not well characterized, while it may be the mechanism responsible for the metabolites' lack of activity. Methods In this study recombinant ABCB1 ATPase transporter assay; anthracyclines accumulation assay in resistant cells overexpressing ABCB1; and molecular modeling were used to investigate anthracyclines: doxorubicin and daunorubicin and their carbonyl-reduced metabolites (doxorubicinol, daunorubicinol) susceptibility for ABCB1-dependent efflux. Results Based on the kinetics parameters of ATPase activity of ABCB1, it was found that daunorubicinol exerted an exceptionally high potential for being effluxed by the ABCB1 transporter. ABCB1 was found to significantly affect the accumulation pattern of studied chemicals in resistant cancer cells. Doxorubicin and daunorubicin accumulation was influenced by the activity of ABCB1 modulator – valspodar. Conclusions Results indicate that ABCB1 activity affects not only anthracyclines but also their metabolites. The effect of ABCB1 on metabolites may be even higher than for parent anthracyclines. Therefore crosstalk between the process of anthracyclines metabolism and metabolites efflux may be the mechanism of impairing anticancer properties of anthracyclines metabolites.