title: Pervilleine F, a new tropane alkaloid aromatic ester that reverses multidrug resistance.
abstract: 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.
authors.affiliation: Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Qiuwen
authors.initials: Q
authors.lastname: Mi
authors.forename: Baoliang
authors.initials: B
authors.lastname: Cui
authors.forename: Daniel
authors.initials: D
authors.lastname: Lantvit
authors.forename: Eulenia
authors.initials: E
authors.lastname: Reyes-Lim
authors.forename: Heebyung
authors.initials: H
authors.lastname: Chai
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Kinghorn
authors.forename: Steven M
authors.initials: SM
authors.lastname: Swanson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D004952:Esters / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy*; D014326:Tropanes / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004952:Esters; C481350:Pervilleine F; D014326:Tropanes; D014747:Vinblastine; D014700:Verapamil