title: Pervilleines B and C, new tropane alkaloid aromatic esters that reverse the multidrug-resistance in the hollow fiber assay.
abstract: P-Glycoprotein (Pgp)-mediated drug efflux can yield a multidrug-resistance phenotype that is associated with poor response to cancer chemotherapy. Pervilleines B and C (PB and PC), two new tropane alkaloid aromatic esters obtained from a chloroform extract of the roots of Erythroxylum pervillei as the result of bioactivity-guided fractionation, were found to restore the vinblastine (VLB) sensitivity of cultured multidrug-resistant KB-V1 cells, with 50% inhibitory concentration values of 0.17 microM in each case. To explore the potential relevance of this response, KB-V1 cells were placed in hollow fibers and implanted into NCr nu/nu mice. Cell growth was not significantly inhibited when VLB or PB or PC were administered as single agents, but when used in combination with vinblastine inhibition of up to 77.7% was observed. Equimolar doses of verapamil were less effective. These data suggest that PB and PC are effective inhibitors of Pgp and should be further evaluated for clinical utility.
authors.affiliation: Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy (m/c 877), 833 South Wood Street, University of Illinois at Chicago, 60612, USA.
authors.forename: Qiuwen
authors.initials: Q
authors.lastname: Mi
authors.forename: Baoliang
authors.initials: B
authors.lastname: Cui
authors.forename: Gloria L
authors.initials: GL
authors.lastname: Silva
authors.forename: Daniel
authors.initials: D
authors.lastname: Lantvit
authors.forename: Eula
authors.initials: E
authors.lastname: Lim
authors.forename: Heebyung
authors.initials: H
authors.lastname: Chai
authors.forename: Melinda G
authors.initials: MG
authors.lastname: Hollingshead
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Mayo
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Kinghorn
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007624:KB Cells / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D014326:Tropanes / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D014326:Tropanes; C467799:pervilleine B; C467798:pervilleine C; D014747:Vinblastine