TY - JOUR
T1 - Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction
AU - Samudio, Ismael
AU - Harmancey, Romain
AU - Fiegl, Michael
AU - Kantarjian, Hagop
AU - Konopleva, Marina
AU - Korchin, Borys
AU - Kaluarachchi, Kumar
AU - Bornmann, William
AU - Duvvuri, Seshagiri
AU - Taegtmeyer, Heinrich
AU - Andreeff, Michael
PY - 2010/1/4
Y1 - 2010/1/4
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI38942
DO - 10.1172/JCI38942
M3 - Article
C2 - 20038799
AN - SCOPUS:74949089659
SN - 0021-9738
VL - 120
SP - 142
EP - 156
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -