title: Reversal of acquired resistance to doxorubicin in K562 human leukemia cells by astemizole.
abstract: This study demonstrates that astemizole, a non-sedating anti-histaminergic drug with low toxicity in vivo, greatly potentiates the growth-inhibitory activity of doxorubicin in doxorubicin-resistant human leukemia cells (K562/DXR). Astemizole synergistically potentiated the cytotoxicity of doxorubicin for K562/DXR cells at a concentration of 0.1-3 microM in a dose-dependent manner, whereas they showed hardly any synthergistic effect in the parental cell line (K562) at the same concentration. Since doxorubicin resistance in these cells is associated with the expression of high levels of P-glycoprotein, we evaluated the effect of astemizole on P-glycoprotein activity in cytofluorographic efflux experiments with doxorubicin. Our results indicate that astemizole inhibits the P-glycoprotein pump-efflux activity in a dose-related manner. Moreover, it also inhibits the photolabeling of P-glycoprotein by [3H]azidopine in a dose-dependent manner. These findings provide a biological basis for the potential therapeutic application of astemizole as an anticancer drug either alone or in combination with doxorubicin to multidrug-resistant leukemic cells.
authors.affiliation: Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University, Sendai, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ishikawa
authors.forename: R
authors.initials: R
authors.lastname: Fujita
authors.forename: M
authors.initials: M
authors.lastname: Takayanagi
authors.forename: Y
authors.initials: Y
authors.lastname: Takayanagi
authors.forename: K
authors.initials: K
authors.lastname: Sasaki
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016589:Astemizole / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001386:Azides / Q000037:antagonists & inhibitors / Q000378:metabolism; D003124:Colorimetry; D004095:Dihydropyridines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D020014:K562 Cells / Q000187:drug effects* / Q000378:metabolism; D019920:Photoaffinity Labels / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001386:Azides; D004095:Dihydropyridines; D019920:Photoaffinity Labels; C041130:azidopine; D016589:Astemizole; D004317:Doxorubicin