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Pervilleine A, a Novel Tropane Alkaloid that Reverses the Multidrug-resistance Phenotype¹

Program for Collaborative Research in the Pharmaceutical Sciences and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612 [Q. M., B. C., G. L. S., D. L., E. L., H. C., M. Y., A. D. K., J. M. P.], and Biological Testing Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21701 [M. G. H., J. G. M.]

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 KB-V1 and CEM/VLB₁₀₀ cells, with IC₅₀ values of 0.36 and 0.02 µM, respectively. Similarly, the chemosensitivity of KB-8-5 cells to colchicine was restored with an IC₅₀ value of 0.61 µM. The mechanism of this response was evaluated with a number of model systems. First, incubation of multidrug-resistant KB-V1 and CEM/VLB₁₀₀ cells with up to 45 µM 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 [³H]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 K_i of 7.3 µM. Consistent with this effect, intracellular accumulation of [³H]vinblastine was increased from 0.18 pmol [³H]vinblastine/50 x 10⁴ cells to approximately 5 pmol [³H]vinblastine/50 x 10⁴ cells in the presence of 40 µM pervilleine A. To explore the potential relevance of these responses, KB-V1 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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