Pervilleine A, a novel tropane alkaloid that reverses the multidrug-resistance phenotype

P-Glycoprotein-mediated drug efflux can yield a multidrug- resistance (MDR) phenotype that is associated with a poor response to cancer chemotherapy, Pervilleine A, a novel tropane alkaloid obtained from a chloroform extract of Erythroxylum pervillei as the result of bioactivity-guided fractionation, was found to restore the vinblastine sensitivity of cultured multidrug-resistant I(B-VI and CEM/VLB100 cells, with IC50 values of 0.36 and 0.02 muM, respectively. Similarly, the chemosensitivity of KB-8-5 cells to colchicine was restored with an IC50 value of 0.61 muM The mechanism of this response was evaluated with a number of model systems. First, incubation of multidrug-resistant KB-VI and CEM/VLB100 cells with up to 45 muM pervilleine A for 72 h did not significantly affect either the transcription of MDR1, as revealed by reverse transcriptional-PCR-based analysis of MDR1 mRNA, or levels of P-glycoprotein, as shown by Western blots. ATP-dependent binding of [H-3]vinblastine observed with isolated multidrug- resistant KB-V1 cell membrane vesicles was inhibited by pervilleine A in a dose-dependent manner, and kinetic analysis indicted competitive inhibition with respect to vinblastine binding with a Ki of 7.3 muM. Consistent with this effect, intracellular accumulation of [H-3]vinblastine was increased from 0.18 pmol [H-3]vinblastine/50 x 10(4) cells to approximately 5 pmol [H-3]vinblastine/50 x 10(4) cells in the presence of 40 muM pervilleine A. To explore the potential relevance of these responses, KB-VI or KB-8-5 cells were placed in hollow fibers and implanted into NCr nu/nu mice. Cell growth was not significantly inhibited when vinblastine or pervilleine A were administered as single agents, but when used in combination, inhibition of up to 75% was observed. Equimolar doses of verapamil were less effective. These data suggest that pervilleine A is an effective inhibitor of P-glycoprotein and should be further evaluated for clinical utility.

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