Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction
Ismael Samudio, … , Heinrich Taegtmeyer, Michael Andreeff
Ismael Samudio, … , Heinrich Taegtmeyer, Michael Andreeff
Published December 21, 2009
Citation Information: J Clin Invest. 2010;120(1):142-156. https://doi.org/10.1172/JCI38942.
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Research Article Hematology

Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

Abstract

The traditional view is that cancer cells predominately produce ATP by glycolysis, rather than by oxidation of energy-providing substrates. Mitochondrial uncoupling — the continuing reduction of oxygen without ATP synthesis — has recently been shown in leukemia cells to circumvent the ability of oxygen to inhibit glycolysis, and may promote the metabolic preference for glycolysis by shifting from pyruvate oxidation to fatty acid oxidation (FAO). Here we have demonstrated that pharmacologic inhibition of FAO with etomoxir or ranolazine inhibited proliferation and sensitized human leukemia cells — cultured alone or on bone marrow stromal cells — to apoptosis induction by ABT-737, a molecule that releases proapoptotic Bcl-2 proteins such as Bak from antiapoptotic family members. Likewise, treatment with the fatty acid synthase/lipolysis inhibitor orlistat also sensitized leukemia cells to ABT-737, which supports the notion that fatty acids promote cell survival. Mechanistically, we generated evidence suggesting that FAO regulates the activity of Bak-dependent mitochondrial permeability transition. Importantly, etomoxir decreased the number of quiescent leukemia progenitor cells in approximately 50% of primary human acute myeloid leukemia samples and, when combined with either ABT-737 or cytosine arabinoside, provided substantial therapeutic benefit in a murine model of leukemia. The results support the concept of FAO inhibitors as a therapeutic strategy in hematological malignancies.

Authors

Ismael Samudio, Romain Harmancey, Michael Fiegl, Hagop Kantarjian, Marina Konopleva, Borys Korchin, Kumar Kaluarachchi, William Bornmann, Seshagiri Duvvuri, Heinrich Taegtmeyer, Michael Andreeff

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Figure 1

Leukemia cells uncouple FAO from ATP synthesis and rely on de novo FAS to support FAO.

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Leukemia cells uncouple FAO from ATP synthesis and rely on de novo FAS t...
(A) Schematic representation of the relevant metabolic pathways investigated. α-KG, α-ketoglutarate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase. (B) OCI-AML3 and MOLM13 cells were grown alone or on MSC feeder layers as described in Methods, and after MACS depletion of MSCs, 2 × 105 leukemia cells/well were treated with increasing concentrations of EX and monitored for oxygen consumption in Oxygen Biosensor plates for 3 hours. (C) OCI-AML3 cells were grown as in B and treated with 2-DG (5.5 and 11 mmol/l) or EX (100 and 200 μmol/l) for 6 hours, and after MACS depletion of MSCs, 2 × 105 leukemia cells were lysed, and ATP levels were quantitated as described in Methods. (D) OCI-AML3 and MOLM13 cells were grown alone or on MSC feeder layers and exposed to increasing concentrations of EX for 48 hours. The number of viable cells (Annexin V–negative; tetramethyl-rhodamine methyl ester–positive) and lactate levels were quantitated as described in Methods; results are expressed as picomoles lactate per viable cell. (E) Leukemia cells were cultured as in B, treated with increasing concentrations of orlistat, and monitored for oxygen consumption in Oxygen Biosensor plates for 3 hours. *P < 0.005, **P < 0.01 versus monocultures; #P < 0.005 versus control.