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Pervilleine F, a new tropane alkaloid aromatic ester that reverses multidrug resistance.

P-glycoprotein (Pgp)-mediated drug efflux can yield a multidrug resistance (MDR) phenotype that is associated with poor response to cancer chemotherapy. Pervilleine F, a new tropane alkaloid aromatic ester obtained from a chloroform extract of the roots of Erythroxylum pervillei as the result of bioactivity-guided fractionation, was found to restore the vinblastine sensitivity of cultured multidrug-resistant KB-V1 cells, with an IC50 value of 0.40 microM. Pervilleine F (8 microM) was also able to partially reverse the cross-resistance of KB-V1 cells to the clinically used or experimental anticancer agents actinomycin D (45.1-fold), baccatin III (> 3.4-fold), daunomycin (> 22.5-fold), ellipticine (1.9-fold), mithramycin A (42.5-fold), podophyllotoxin (1.6-fold), paclitaxel (32.2-fold) and vincristine (73.6-fold). While pervilleine F alone at the concentration of 10 microM had no significant effect on the KB-V1 cell cycle, pervilleine F (at concentrations of 0.2, 1, 2, and 8 microM) combined with vinblastine (1 microgram/ml) induced dose-dependent G2/M phase arrest, ranging from 20.2, 51.0, 63.7, to 79.5%, as an indication of the restoration of vinblastine sensitivity. To confirm this activity with an in vivo animal model, KB-V1 cells were placed in hollow fibers and implanted into NCr nu/nu mice. Cell growth was not significantly inhibited when vinblastine or pervilleine F was administered as single agents, but when these two compounds were used in combination, inhibition of up to 64.1% was observed. Equimolar doses of verapamil were less effective. These data suggest that pervilleine F is an effective inhibitor of Pgp and should be further evaluated for clinical utility.