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• W1504133502 abstract "Abstract : The hypothesis of this study is that glucosylceramide synthase (GCS)-governed drug resistance can be acquired through exposure to ceramide-generating anticancer agents(e.g., Adriamycin, paclitaxel, and etoposide). We have shown that paclitaxel, Adriamycin, and SDZ PSC 833 induce ceramide generation in MCF-7 cells (200, 83, and 900%, respectively, at 24h). Paclitaxel and SDZ PSC 833 increased ceramide levels by 192 and 460%, respectively, at 24h in MDA-MB-231 cells. The ceramide generated by Paclitaxel and SDZ PSC 833 is metabolized to glucosylceramide (GC) (54 and 200%, respectively, in MCF7 cells at 24h; 172 and 307%, respectively, at 24h in MDA-MB-231 cells). When wild-type breast cancer cells such as MCF-7 and MDA-MB-231 are exposed to a low concentration of [14C]C6-ceramide (0.2 g/ml), cells converted it to sphingomyelin. However, when breast cancer cells are challenged with a higher concentration of [14C]C6-ceramide (5 g/ml), ceramide was glucosylated to GC via GCS. Acute exposure of MCF-7 and MDA-MB-231 cells to C8-GC (10 g/ml) for 72h increased MDR1 expression by 2- and 4-fold, respectively. Chronic exposure of MDA-MB-231 cells to C8-ceramide for extended periods induced a dramatic increase in MDR1 mRNA levels, and also elicited expression of P-glycoprotein. High passage C8-ceramide-grown MDA-MB-231 cells were more resistant to Adriamycin and paclitaxel. These experiments show that high levels of ceramide enhance expression of the MDA phenotype in cancer cells through what we propose is a GC intermediate. We then studied another major avenue of ceramide elimination, hydrolysis via ceramidase (CDase). In MCF-7NP (etoposide resistant) and MCF-7/CDDP (cisplatin resistant) compared to MCF-7 cells, alkaline CDase increased by 2- and 34old, respectively, and in MCF-7/AdrR cells, neutral CDase increased by 3.4-fold. This result suggests that CDase could be implicated also in the drug-resistant phenotype." @default.
• W1504133502 created "2016-06-24" @default.
• W1504133502 creator A5061529190 @default.
• W1504133502 date "2005-05-01" @default.
• W1504133502 modified "2023-10-03" @default.
• W1504133502 title "Mechanisms of Chemoresistance in Breast Cancer Cells" @default.
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• W1504133502 doi "https://doi.org/10.21236/ada435635" @default.
• W1504133502 hasPublicationYear "2005" @default.
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