In Vitro And In Vivo Reversal Of Multidrug Resistance Induced By GCS In Breast Cancer By RNA Interference

Background: Multidrug resistance(MDR) is characterized by a cross-resistant phenotype against several unrelated drugs that differ widely with respect to molecular structure and target specificity. It is the major cause of the failure of chemotherapy-based treatment modalities of malignant tumors. The mechanisms of MDR always exist at the same time and one mechanism acts upon another. In recent years, researchers put more attention to the relationship between apoptosis induced by Glucosylceramide synthase (GCS) and MDR.GCS, the enzyme that converts ceramide to glucosylceramide, prevents cells from apoptosis induced by ceramide and plays a principle role in multidrug resistance of cancer cells. Ceramide, a second messenger in cellular apoptotic signaling, has shown to participate in reactions to chemotherapy and radiotherapy of cancer. Loss of ceramide production is one reason of cellular resistance to apoptosis induced by tumor necrosis factor a, adriamycin or ionizing radiation. The levels of glucosylceramide (GlcCer), a simple glycosylated form of ceramide, are elevated in some multidrug-resistant cancer cells. Decreasing the potential for ceramide glycosylation has been shown to overcome resistance to several classes of anticancer drugs. Pharmocologically active compounds could limit GCS activity and enhance ceramide generation, such as PPPP (1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1- propanol), PDMP (1-phenyl-2-dsdecanoyIarnino-3-morphoIino-1-propanol) and cyclosporin A. They increased cancer cell sensitivity to antineoplastic agents. In clinical trials,...