Reversal of P-glycoprotein-mediated multidrug resistance in vitro by AV200, a new ardeemin derivative.
The activity of AV200, a synthetic ardeemin derivative, in reversing the multidrug resistance phenotype has been investigated. At non-toxic doses, AV200 was able to completely restore vincristine and paclitaxel toxicities and partially restore that of doxorubicin in multidrug-resistant cells. The potency of AV200 as a modulator of the resistance to doxorubicin, vincristine and paclitaxel resulted to be seven-, 59 and 12-fold, respectively, higher than that of verapamil. In vitro measurements of rhodamine 123 accumulation in human resistant cells suggest that AV200 reverses multidrug resistance by directly inhibiting the P-glycoprotein-mediated drug efflux. This work underscores the possibility of utilizing ardeemin derivatives as a source of non-toxic modulators of the multidrug resistance phenotype.
Méndez-Vidal
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Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Málaga, Spain.
Quesada
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C119983:AV200; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D006575:Heterocyclic Compounds, 3-Ring; D020112:Rhodamine 123; D014750:Vincristine; D004317:Doxorubicin; D014700:Verapamil; D017239:Paclitaxel