The multidrug resistance modulator SDZ PSC 833 is a potent activator of cellular ceramide formation.
In this study we demonstrate that the multidrug resistance (MDR) modulator PSC 833 is a potent agonist of ceramide metabolism. When added with [3H]serine or [3H]palmitic acid to the culture medium of MCF-7 cells, PSC 833, in a dose-responsive fashion (1-10 microM), increased the levels of [3H]ceramide as much as 16-fold over control. The actual increase in ceramide mass was verified by thin-layer chromatographic chars. Cellular sphingomyelin radioactivity did not decrease during treatment, indicating that PSC 833 does not elicit ceramide formation through a sphingomyelinase pathway. Inclusion of fumonisin B1, an inhibitor of ceramide synthase, blocked formation of ceramide by PSC 833. The results of cell proliferation assays demonstrated a clear correlation between PSC 833 elicitation of ceramide formation and increased cytotoxicity. The MDR modulator and chemical cousin of PSC 833, cyclosporin A, had little impact on cellular ceramide formation. At a concentration of 2.5 microM, cyclosporin A and PSC 833 treatment increased ceramide formation by 20% and 7.5-fold, respectively. These results reveal a new action of PSC 833 which may contribute to its potency as a drug resistance modulator.
John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA. cabot@jwci.org
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Cabot
T Y
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Han
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Giuliano
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000819:agonists / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D006801:Humans; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002518:Ceramides; D003524:Cyclosporins; D016572:Cyclosporine; C070272:valspodar