PP178. CIRCUMVENTING MULTI-DRUG RESISTANCE BY A COMBINATION THERAPY OF IMATINIB AND GCS INHIBITOR IN IMATINIB-RESISTANT HUMAN CHRONIC MYELOID LEUKEMIA CELLS
YUSUF BARAN1,2, Ufuk Gündüz1, Jacek Bielawski2, Besim Öğretmen2. 1. Middle East Technical University, Department of Biology, TURKEY. 2. Medical University of South Carolina, Department of Biochemistry and Molecular Biology, USA. e-mail: ybaran@metu.edu.tr
*Corresponding Author:
page: 127

Abstract

Ceramide lipids have recently emerged as intracellular signaling molecules involved in mediating cell death. Increases in intracellular ceramide levels and subsequent apoptosis have been observed in response to treatment with agents such as Fas ligand, environmental insults such as UV, and exposure to cytotoxic agents such as chemotherapeutics. Although ceramide is a proapoptotic lipid, its glucosyl-ceramide metabolite is not. Thus, conversion of ceramide to glucosyl-ceramide by the glucosylceramide synthas (GCS) is a mechanism by which cells can lower intracellular ceramide levels and thus avoiding apoptosis. 1-phenyl-2-decanoylamino-3-morpholino-1-propanol is a well-known inhibitor of the GCS that has been shown to decrease glucosyl-ceramide production and promote ceramide accumulation in the cells. Imatinib is an anticancer agent used commonly in treatment of chronic myeloid leukemia (CML). The effect of the GCS inhibitor on the chemosensitivity of CML cells was investigated. Sensitive (K562 and Meg-01) and imatinib-resistant (K562/IMA-1 and Meg-01/IMA-1) cells were exposed to sub-toxic concentrations of GCS inhibitor in the absence or presence of imatinib. Intracellular concentrations of ceramides were detected by liquid chromotography/mass spectrometry. Percent of cell population in apoptosis were determined by flow cytometry in response to GCS inhibitor and imatinib. Results revelaed that there were a significant increase in ceramide accumulation and also in apoptosis in GCS inhibitor and imatinib exposed sensitive and resistant cells as comparing to only imatinib exposed cells. These observations suggest that inhibiting ceramide glycosylation keeps the intracellular ceramide levels elevated, which results in apoptosis. Inhibiton of GCS is potential approach for circumventing MDR.




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