Inhibitors of cancer cell multidrug ABC transporters: Extrapolation to combat Candida albicans resistance to antifungals

Abstract

A number of human cancer cells become resistant to anticancer agents upon overexpression of three main membrane ATP-binding cassette (ABC) multidrug transporters, ABCB1, ABCG2 and ABCC1, of which inhibitors have been identified. Similarly, Candida albicans may become resistant to antifungals upon overexpression of the CaCrd1p ABC transporter. Structural and functional analyses of CaCdr1p indicate common features with the three human multidrug ABC transporters: same degenerescence of ATP-binding motifs as ABCC1, same "reverse" topology as ABCG2, and comparable pattern of hydrophobic, nonconjugated, substrates as ABCB1. Assaying representative inhibitors of the different human multidrug ABC transporters indicated that only those targeting ABCB1 were efficient against CaCdr1p transport activity. Potent inhibitors, able to prevent Nile Red efflux from a Saccharomyces cerevisia strain transformed to overexpress CaCdr1p and to sensitize its growth to fluconazole, were identified among macrocyclic diterpenes such as jatrophanes and lathyranes, and among other classes of compounds known to interact with ABCB1, but with different structure-activity relationships. Interestingly, other derivatives from the same series and other classes of compounds were able to inhibit CaMdr1p, a non-ABC multidrug transporter of Candida albicans, belonging to the Major Facilitator Superfamily (MFS) and overexpressed concomitantly to CaCdr1p in antifungal-resistant strains.