Mechanism of action of dexniguldipine-HCl (B8509-035), a new potent modulator of multidrug resistance

• Published in: Biochemical pharmacology 1995-03, Vol.49 (5), p.603-609
• Main Authors: Hofmann, Johann, Gekeler, Volker, Ise, Wolfgang, Noller, Andrea, Mitterdorfer, Jörg, Hofer, Susanne, Utz, Irene, Gotwald, Markus, Boer, Rainer, Glossmann, Hartmut, Grunicke, Hans H.
• Format: Article
• Language: English
• Subjects: Affinity Labels; Antineoplastic agents; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Azides - metabolism; B8509-035; Biological and medical sciences; Cell Line - drug effects; Cell Survival - drug effects; dexniguldipine-HCl; Dihydropyridines - metabolism; Dihydropyridines - pharmacology; DNA Topoisomerases, Type II - genetics; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; Drug Interactions; Drug Resistance, Multiple - genetics; General aspects; Humans; Medical sciences; multidrug resistance; Pharmacology. Drug treatments; Rhodamine 123; Rhodamines - metabolism; Transfection; Vincristine - pharmacology
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/0006-2952(94)00479-6

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 μM 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. ic 50 drug/ ic 50 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.