Pharmacological Inhibition of Fatty Acid Oxidation as a Novel Therapeutic Concept for Acute Myeloid Leukemia.

Abstract 3779

Poster Board III-715

Otto Warburg proposed that the origin of cancer cells was closely linked to a permanent respiratory defect that bypassed the Pasteur effect, i.e. the inhibition of anaerobic fermentation by oxygen. We have recently demonstrated in leukemia cells that mitochondrial uncoupling, i.e. the abrogation of ATP synthesis in response to mitochondrial membrane potential (MMP), promotes the Warburg effect, contributes to chemo-resistance and represents a metabolic shift to fatty acid oxidation (FAO). Exposure of leukemic cells to marrow-derived mesenchymal stromal cells (MSC) promotes accumulation of lactate and reduces MMP. Stroma/leukemia co-cultures protect leukemia cells from chemotherapy-induced apoptosis. We found that he decrease in MMP was mediated by mitochondrial uncoupling accompanied by increased expression of mitochondrial uncoupling protein (UCP2) (Cancer Res. 68:5198,2008). We therefore proposed that the Warburg effect may be the result of preferential oxidation of fatty acids in cancer cell mitochondria (Cancer Res.69:2163,2009). Here we demonstrate that leukemia cells uncouple FAO from ATP synthesis, and that pharmacological inhibition of FAO with etomoxir or ranolazine inhibits proliferation and sensitizes leukemia cells – cultured alone or on bone marrow stromal cells – to apoptosis induction by the BH3 mimetic ABT-737 and the MDM-2 antagonist Nutlin 3a. Results suggest that leukemia cells rely, at least in part, on de novo fatty acid synthesis (FAS) to support FAO. Furthermore, treatment with the FAS inhibitor orlistat sensitized leukemia cells to apoptosis induction by ABT-737. Mechanistically, mitochondria derived from etomoxir treated leukemia cells were sensitized to release of cytochrome C and apoptosis-inducing-factor (AIF) upon treatment with ABT-737. Etomoxir (EX) facilitated the formation of Bak oligomers after treatment with ABT-737 suggesting that FAO regulates the activity of Bak-dependent mitochondrial permeability transition. Lastly, we present evidence that EX, in combination with liposomal ABT-737 or cytosine arabinoside (AraC), provides significant therapeutic benefit in a murine model of human leukemia (luciferase/GFP marked MOLT13 cells) as evidenced by reduced in vivo growth kinetics (BLI) and prolonged median survival (ABT-737 vs. EX+ABT-737, p=<0.05; AraC vs.EX+AraC,p<0.0001 ). Conclusions: 1) results support the notion that the Warburg effect may be the result of preferential oxidation of fatty acids by leukemia mitochondria. 2) Inhibition of fatty acid oxidation is proposed as a novel therapeutic concept for hematological malignancies.