Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>While significant progress has been made in understanding the genetics of AML, treatment still consists of induction therapy that is toxic and not tolerated by the elderly. In this study we show in cell culture models that manipulating sphingolipid metabolism may provide a potential mechanism to increase the efficacy of induction therapy, thus possibly allowing the use of lower doses of cytotoxic chemotherapy while maintaining efficacy. Recently thousands of papers have revealed that sphingolipid metabolism has a major role in determining how a diverse group of cell types, including myeloid malignancies, respond to a variety of stresses, particularly chemotheraputics, through production of the pro-apoptotic lipid ceramide. Conversely, a downstream ceramide metabolite, sphingosine-1-phosphte (S1P), has been shown to have the opposite effect, promoting survival, multi-drug resistance, and proliferation. We hypothesize that through the use of small molecules that inhibit the metabolism of ceramide and the formation of S1P we can decrease the apoptotic threshold of leukemic cells. To investigate this we used inhibitors to two enzymes that metabolize ceramide, the ceramidase inhibitor, LCL-385, and the glucosylceramide synthase inhibitor, PDMP, as well as the sphingosine kinase inhibitor, SKI, alone and in combination with daunorubicin and cytarabine in common AML cell culture models, HL-60 and HEL. We found that at low nanomolar concentrations each of these inhibitors alone dramatically decreases proliferation and increases apoptosis in both cell types in a dose dependant manner. Most importantly, through analysis with the Chou and Talalay combination index model, we have shown that each of these molecules works synergistically with daunorubicin and cytarabine (see table below). This data highlights the importance of sphingolipid metabolism in the response of AML cells to chemotherapy and as a potential synergistic target for induction therapy.</jats:p>
<jats:p>Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-165. doi:1538-7445.AM2012-LB-165</jats:p>