Reversal of P-glycoprotein-mediated multidrug resistance in vitro by AV200, a new ardeemin derivative.

The activity of AV200, a synthetic ardeemin derivative, in reversing the multidrug resistance phenotype has been investigated. At non-toxic doses, AV200 was able to completely restore vincristine and paclitaxel toxicities and partially restore that of doxorubicin in multidrug-resistant cells. The potency of AV200 as a modulator of the resistance to doxorubicin, vincristine and paclitaxel resulted to be seven-, 59 and 12-fold, respectively, higher than that of verapamil. In vitro measurements of rhodamine 123 accumulation in human resistant cells suggest that AV200 reverses multidrug resistance by directly inhibiting the P-glycoprotein-mediated drug efflux. This work underscores the possibility of utilizing ardeemin derivatives as a source of non-toxic modulators of the multidrug resistance phenotype.