Conferone from Ferula schtschurowskiana enhances vinblastine cytotoxicity in MDCK-MDR1 cells by competitively inhibiting P-glycoprotein transport.
Overexpression of the protein transporter P-glycoprotein (Pgp, MDR1) at the cell surface is a major cause of multidrug resistance (MDR) and poor response to treatment in cancer chemotherapy and therapy for leishmaniasis. The present study shows that conferone, a sesquiterpene coumarin ether isolated for the first time from Ferula schtschurowskiana, endemic in Uzbekistan, enhances the cell toxicity of vinblastine (VBL) in MDR1-transfected Madin-Darby canine kidney (MDCK-MDR1) cells. Conferone presents the advantage to mediate this effect at safe concentrations. At 10 microM, it efficiently competes with the photoactivatable cyclosporin A analogue (SDZ 212 - 122) for the binding to Pgp and accumulates [3H]-VBL to a higher extent than cyclosporin A or cnidiadin. [3H]-VBL accumulation is dose-dependent and correlates with the inhibition of Pgp photolabeling affinity, supporting the hypothesis that conferone sensitizes MDCK-MDR1 cells to VBL by competitively inhibiting drug efflux. In MDCK-MDR1 cells, [3H]-VBL accumulation appears to be almost completely dependent on inhibition of Pgp transport. However, the strict specificity of conferone to this efflux pump has to be demonstrated in cell lines expressing other protein transporters. Collectively, our findings identify conferone as a powerful modulator of Pgp transport and a promising molecule for the treatment of MDR malignancies and leishmaniasis. Complementary in vitro and in vivo studies are, however, needed to assess the value of conferone as a reversal drug in human therapy. Considering its high affinity for Pgp, conferone may have an additional usefulness as a tool for the design or the (hemi)synthesis of agents probing Pgp. To our knowledge, this is the first report identifying sesquiterpene coumarins from Ferula as possible drug candidates for the reversion of MDR encoded by the MDR1 gene or the synthesis of agents probing Pgp.
Barthomeuf
Chantal
C
UMR: INSERM U-484, Université d'Auvergne, Centre hospitalier J. Perrin, Laboratoire de Pharmacognosie et de Biotechnologie, Faculté de Pharmacie, Clermont-Ferrand, France. chantal.barthomeuf@u-clermont1.fr
Demeule
Michel
M
Grassi
Jérôme
J
Saidkhodjaev
Ashraf
A
Beliveau
Richard
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000277:Adjuvants, Pharmaceutic / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003374:Coumarins / Q000302:isolation & purification / Q000494:pharmacology*; D016572:Cyclosporine; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005309:Ferula / Q000737:chemistry*; D019450:Genes, MDR; D006801:Humans; D019920:Photoaffinity Labels; D014316:Tritium; D014747:Vinblastine / Q000493:pharmacokinetics / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000277:Adjuvants, Pharmaceutic; D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; D019920:Photoaffinity Labels; C513235:conferone; D014316:Tritium; D014747:Vinblastine; D016572:Cyclosporine