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 KB-V1 and CEM/VLB(100) cells, with IC(50) values of 0.36 and 0.02 microM, respectively. Similarly, the chemosensitivity of KB-8-5 cells to colchicine was restored with an IC(50) value of 0.61 microM. The mechanism of this response was evaluated with a number of model systems. First, incubation of multidrug-resistant KB-V1 and CEM/VLB(100) cells with up to 45 microM 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 [(3)H]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 microM. Consistent with this effect, intracellular accumulation of [(3)H]vinblastine was increased from 0.18 pmol [(3)H]vinblastine/50 x 10(4) cells to approximately 5 pmol [(3)H]vinblastine/50 x 10(4) cells in the presence of 40 microM 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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Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood St., Chicago, IL 60612, USA.
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Silva
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Lantvit
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Lim
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Chai
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Hollingshead
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Mayo
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Kinghorn
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D019450:Genes, MDR / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007624:KB Cells / Q000187:drug effects; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014326:Tropanes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000493:pharmacokinetics / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D014326:Tropanes; C428023:pervilleine A; D014747:Vinblastine; D014700:Verapamil; D003078:Colchicine