title: Rifampicin enhances anti-cancer drug accumulation and activity in multidrug-resistant cells.
abstract: Rifampicin, a semi-synthetic antibiotic used in the treatment of tuberculosis and belonging to the chemical class of rifamycins, was examined for its effect on anti-cancer drug accumulation and activity in multidrug resistant cells overexpressing P-glycoprotein (P-gp). Rifampicin was shown to strongly enhance vinblastine accumulation in both rat hepatoma RHC1 and human leukemia K562 R7 multidrug resistant cells, but had no effect in rat SDVI drug-sensitive liver cells. By contrast, two other rifamycins, rifamycins B and SV, had no or only minor effect on vinblastine accumulation in RHC1 cells. Efflux experiments revealed that rifampicin was able, like the well-known chemosensitizer agent verapamil, to decrease export of vinblastine out of resistant cells. Rifampicin, when used at a concentration close to plasma concentrations achievable in humans (25 microM), was able to increase sensitivity of RHC1 cells to both vinblastine and doxorubicin. Rifampicin was also demonstrated to inhibit P-gp radiolabeling by the photoactivable P-gp ligand azidopine, thereby suggesting that the antituberculosis compound can interfere directly with P-gp drug binding sites. These results thus indicate that rifampicin was able to down-modulate P-gp-associated resistance through inhibition of P-gp function.
authors.affiliation: Unité de Recherches Hépatologiques U 49 de l'INSERM, Hôpital de Pontchaillou, Rennes, France.
authors.forename: O
authors.initials: O
authors.lastname: Fardel
authors.forename: V
authors.initials: V
authors.lastname: Lecureur
authors.forename: P
authors.initials: P
authors.lastname: Loyer
authors.forename: A
authors.initials: A
authors.lastname: Guillouzo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D006801:Humans; D051381:Rats; D012293:Rifampin / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014747:Vinblastine / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D014747:Vinblastine; D004317:Doxorubicin; D012293:Rifampin