title: 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.affiliation: Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Ismael
authors.initials: I
authors.lastname: Samudio
authors.forename: Romain
authors.initials: R
authors.lastname: Harmancey
authors.forename: Michael
authors.initials: M
authors.lastname: Fiegl
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Borys
authors.initials: B
authors.lastname: Korchin
authors.forename: Kumar
authors.initials: K
authors.lastname: Kaluarachchi
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.forename: Seshagiri
authors.initials: S
authors.lastname: Duvvuri
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000627:therapeutic use; D049109:Cell Proliferation; D003561:Cytarabine / Q000627:therapeutic use; D064429:Fatty Acid Synthases / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000502:physiology; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000502:physiology; D009596:Nitrophenols / Q000627:therapeutic use; D010084:Oxidation-Reduction; D010879:Piperazines / Q000627:therapeutic use; D017382:Reactive Oxygen Species; D013449:Sulfonamides / Q000627:therapeutic use; D000071246:Uncoupling Protein 2; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry; D051028:bcl-2-Associated X Protein / Q000737:chemistry
chemical_list: C501332:ABT-737; C494772:BAK1 protein, human; C494826:BAX protein, human; D001713:Biphenyl Compounds; D005227:Fatty Acids; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D009596:Nitrophenols; D010879:Piperazines; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D000071246:Uncoupling Protein 2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D003561:Cytarabine; D000255:Adenosine Triphosphate; D064429:Fatty Acid Synthases