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John Wayne Cancer Institute, Saint John’s Health Center, Santa Monica, California 90404

SDZ PSC 833 (PSC 833), a P-glycoprotein-targeted multidrug resistance modulator, sensitizes cancer cells to chemotherapy. Here we show that PSC 833 also potentiates the formation of ceramide. Because ceramide is a second messenger in chemotherapy-induced apoptosis, knowledge of the lipid pathways influenced by PSC 833 is of relevance. In intact MDA-MB 468 breast cancer cells, ceramide generation increased 3-fold 1 h after PSC 833 addition (5.0 µm). Cyclosporine A, a structural analogue, failed to impact ceramide metabolism. Sphinganine, the upstream precursor of ceramide, also increased in response to PSC 833, and this could be blocked by adding L-cycloserine, a serine palmitoyltransferase (SPT) inhibitor. Exposure of cultured cells to PSC 833 (30 min to 4 h; 1–10 µm), followed by isolation of microsomes for in vitro assay, increased SPT activity 60%, whereas palmitoyl CoA synthetase and ceramide synthase activities were not altered. SPT activity was also heightened by pretreating cells with either paclitaxel, N-(4-hydroxyphenyl)retinamide, etoposide, or daunorubicin; however, activation was half that attained by PSC 833. PSC 833 stimulated ceramide generation in other breast cancer cell lines as well, including BT-20, MDA-MB 231, Hs 578T, T-47D, and MCF-7. In summary, several types of anticancer agents and the P-glycoprotein modulator PSC 833 share the ability to increase cellular ceramide levels by activation of SPT, the rate-limiting enzyme in the de novo pathway of ceramide synthesis. These data provide novel insight in the area of lipid-mediated cell death.

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