SDZ 280–125: a cyclopeptolide endowed with an in vitro cyclosporin A-like profile of activity for the reversion of the P-glycoprotein-mediated multidrug resistance of tumor cells

Abstract

Tumor cells whose multidrug resistance is caused by the P-glycoprotein (Pgp) mediated anti-cancer drug (ACD) efflux can be chemosensitized by cyclosporins, whose derivatives were found to display a whole range of resistance-modulating activities. Similarly, derivatives of the non-immunosuppressive natural fungus cyclic peptolide SDZ 90–215 were recently shown to display a broad range of chemosensitizing activities. With highly resistant cells expressing high levels of Pgp, one such compound (SDZ 280–125) was shown here to restore both a normal sensitivity to the growth-inhibitory effects of ACD and a normal retention of an anthracycline antibiotic. With both read-outs, SDZ 280–125 activity was about 3-fold that of cyclosporin A (CsA). SDZ 280–125 also displayed the same profile of chemosensitization as CsA for different ACD classes.