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

Abstract

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.

• Authors: Q Mi, B Cui, G L Silva, D Lantvit, E Lim, H Chai, M You, M G Hollingshead, J G Mayo, A D Kinghorn, J M Pezzuto
• Journal: Cancer research (Cancer Res) Vol. 61 Issue 10 Pg. 4030-7 (May 15 2001) ISSN: 0008-5472 [Print] United States
• PMID: 11358822 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• RNA, Messenger
• Tropanes
• pervilleine A
• Vinblastine
• Verapamil
• Colchicine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, genetics, metabolism)
• Antineoplastic Agents, Phytogenic (pharmacokinetics, pharmacology)
• Blotting, Western
• Cell Division (drug effects)
• Colchicine (pharmacology)
• Drug Resistance, Multiple
• Drug Screening Assays, Antitumor
• Genes, MDR (drug effects)
• Humans
• Inhibitory Concentration 50
• KB Cells (drug effects)
• Phenotype
• RNA, Messenger (biosynthesis, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tropanes (pharmacology)
• Tumor Cells, Cultured (drug effects)
• Verapamil (pharmacology)
• Vinblastine (pharmacokinetics, pharmacology)