Pervilleines B and C, new tropane alkaloid aromatic esters that reverse the multidrug-resistance in the hollow fiber assay.
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.
Mi
Qiuwen
Q
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.
Cui
Baoliang
B
Silva
Gloria L
GL
Lantvit
Daniel
D
Lim
Eula
E
Chai
Heebyung
H
Hollingshead
Melinda G
MG
Mayo
Joseph G
JG
Kinghorn
A Douglas
AD
Pezzuto
John M
JM
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*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D014326:Tropanes; C467799:pervilleine B; C467798:pervilleine C; D014747:Vinblastine