title: Mechanism of action of dexniguldipine-HCl (B8509-035), a new potent modulator of multidrug resistance.
abstract: It has previously been shown that dexniguldipine-HCl (B8509-035) is a potent chemosensitizer in multidrug resistant cells [Hofmann et al., J Cancer Res Clin Oncol 118: 361-366, 1992]. It is shown here that dexniguldipine-HCl causes a dose-dependent reduction of the labeling of the P-glycoprotein by azidopine, indicating a competition of dexniguldipine-HCl with the photoaffinity label for the multidrug resistance gene 1 (MDR-1) product. Exposure to dexniguldipine-HCl results in a dose-dependent accumulation of rhodamine 123 in MDR-1 overexpressing cells. In the presence of 1 microM dexniguldipine-HCl, rhodamine 123 accumulated in multidrug resistant cells to similar levels as in the sensitive parental cell lines. At this concentration, dexniguldipine-HCl enhances the cytotoxicities of Adriamycin and vincristine. The resistance modulating factors (RMF), i.e. IC50 drug/IC50 drug + modulator, were found to be proportional to the expression of MDR-1, ranging from 8 to 42 for Adriamycin and from 16 to 63 for vincristine. Transfection with the MDR-1 gene was found to be sufficient to sensitize cells to the modulation by dexniguldipine-HCl. The compound does not affect the expression of the MDR-1 gene. Dexniguldipine-HCl has no effect on a multidrug resistant phenotype caused by a mutation of topoisomerase II. It is concluded that dexniguldipine-HCl modulates multidrug resistance by direct interaction with the P-glycoprotein.
authors.affiliation: Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Hofmann
authors.forename: V
authors.initials: V
authors.lastname: Gekeler
authors.forename: W
authors.initials: W
authors.lastname: Ise
authors.forename: A
authors.initials: A
authors.lastname: Noller
authors.forename: J
authors.initials: J
authors.lastname: Mitterdorfer
authors.forename: S
authors.initials: S
authors.lastname: Hofer
authors.forename: I
authors.initials: I
authors.lastname: Utz
authors.forename: M
authors.initials: M
authors.lastname: Gotwald
authors.forename: R
authors.initials: R
authors.lastname: Boer
authors.forename: H
authors.initials: H
authors.lastname: Glossmann
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000345:Affinity Labels; D001386:Azides / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000235:genetics; D006801:Humans; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D014162:Transfection; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D001386:Azides; D004095:Dihydropyridines; D012235:Rhodamines; D020112:Rhodamine 123; D014750:Vincristine; C041130:azidopine; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; C054074:niguldipine