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Abstract:
Our previous studies showed that both glucosylceramide synthase (GCS) and P- glycoprotein (P-gp) are overexpressed in Adriamycin-resistant human breast cancer cells, MCF-7-AdrR cells. When these cells were transfected with GCS antisense (asGCS), a stable 30% decrease in GCS activity was obtained. Experiments with paclitaxel (Taxol) showed that intracellular levels of drug were 8.6-fold greater in the asGCS- transfected cell line, MCF-7-AdrR/asGCS, compared to MCF-7-AdrR cells. In assessing p-gp, we observed a dramatic decrease in the level of MDRl expression (80%) by RT-PCR that translated into a similar decrease in P-gp protein levels. To confirm the influence of GCS on MDR1 expression, we inhibited GCS. Treatment of MCF-7-AdrR cells with GCS inhibitor, 1-Phenyl-2-palmitoylamino-3-morpholino-1- propanol (PPMP), or with GCS siRNA, produced a significant decrease in MDR1 mRNA levels compared to untreated. These results were used in manuscript for publication, which showed that P-gp expression can be downregulated by either GCS antisense transfection or chemical inhibition of GCS. In order to determine whether overexpression of GCS is a general characteristic of chemotherapy resistance, we assessed GCS expression and glycolipid levels in Adriamycin-, cisplatin-, etoposide-, and paclitaxel- resistant breast cancer cells.
| Limitations: |
 APPROVED FOR PUBLIC RELEASE |
| Description: |
Annual rept. 1 May 2004-30 Apr 2005 |
| Pages: |
21 |
| Report Date: |
MAY 2005 |
| Contract Number: |
W81XWH-04-1-0491 |
| Report Number: |
A536534 |
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