title: Effects of carvedilol on MDR1-mediated multidrug resistance: comparison with verapamil.
abstract: The reversing effects of carvedilol and other beta-adrenoceptor antagonists on multidrug resistance (MDR) were assessed in HeLa cells and the MDR1-overexpressing derivative Hvr100-6 cells, established by stepwise increases of vinblastine concentration in the culture medium. The inhibitory effects on the transcellular transport and intracellular accumulation of [3H]vinblastine and [3H]daunorubicin were also assessed using LLC-GA5-COL150 cell monolayers, established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells. The cytotoxic effects of vinblastine, paclitaxel, doxorubicin and daunorubicin in Hvr100-6 were reversed 1.4- to 7.1-fold by carvedilol at the realistic clinical concentration of 1 microM, whereas other beta-adrenoceptor antagonists had weaker or no such effects. Transport experiments using LLC-GA5-COL150 cell monolayers demonstrated that this effect of carvedilol was due to the inhibition of MDR1-mediated transport of vinblastine, paclitaxel, doxorubicin and daunorubicin. These MDR1-mediated reversing effects of carvedilol were similar to those of 1 microM verapamil, suggesting that carvedilol could be a candidate modulator of MDR in clinical use. Since other beta-adrenoceptor antagonists had no inhibitory effect on transport, the effects of carvedilol were not related to beta-adrenoceptors and might have been due to antioxidant activity.
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017.
authors.forename: Mikio
authors.initials: M
authors.lastname: Kakumoto
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Kohji
authors.initials: K
authors.lastname: Takara
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kita
authors.forename: Tatsurou
authors.initials: T
authors.lastname: Yagami
authors.forename: Hironao
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Noboru
authors.initials: N
authors.lastname: Okamura
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Okumura
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D003630:Daunorubicin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D004077:Digoxin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D013552:Swine; D014162:Transfection; D014700:Verapamil / Q000494:pharmacology*; D014747:Vinblastine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D002227:Carbazoles; D018076:DNA, Complementary; D011412:Propanolamines; D000077261:Carvedilol; D014747:Vinblastine; D004077:Digoxin; D004317:Doxorubicin; D014700:Verapamil; D017239:Paclitaxel; D005472:Fluorouracil; D003630:Daunorubicin