title: Reversal effects of antifungal drugs on multidrug resistance in MDR1-overexpressing HeLa cells.
abstract: In this study, the antiproliferative effects of vinblastine (VLB), paclitaxel (TXL), doxorubicin (DXR), daunorubicin (DNR) and 5-fluorouracil (5-FU) were assessed in the human cervical carcinoma cell line HeLa-Ohio (HeLa) and Hvr100-6 cells, established by growing the parental HeLa cells in the presence of progressively greater concentrations of VLB in the culture medium. Flow cytometric analysis indicated the induction of MDR1 (P-glycoprotein) in Hvr100-6 cells with no alterations in levels of multidrug resistance-associated protein (MRP). Resistance to VLB, TXL, DXR and DNR was found in Hvr100-6 cells with relative resistances of ca. 300, 4000, 50 and 200, respectively, whereas no resistance was found to 5-FU. The reversal effects of antifungal drugs, fluconazole, itraconazole, ketoconazole, miconazole and amphotericin B on multidrug resistance were also assessed using Hvr100-6 cells. Itraconazole was found to have potent reversal effect on the resistance to VLB and TXL, but the others had no such effect. This reversal effect of itraconazole was concentration-dependent, with dose modifying factors of 3.2, 10.1 and 435.7 at 0.1, 0.25 and 0.5 microM of itraconazole, respectively. In addition, this reversal effect of itraconazole was explained by the inhibition of accumulation of the anticancer drugs.
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Iida
authors.forename: K
authors.initials: K
authors.lastname: Takara
authors.forename: N
authors.initials: N
authors.lastname: Ohmoto
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.forename: A
authors.initials: A
authors.lastname: Wada
authors.forename: M
authors.initials: M
authors.lastname: Hirai
authors.forename: T
authors.initials: T
authors.lastname: Sakaeda
authors.forename: K
authors.initials: K
authors.lastname: Okumura
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000935:Antifungal Agents / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D014747:Vinblastine; D017239:Paclitaxel; D005472:Fluorouracil