PMID- 20038799
OWN - NLM
STAT- MEDLINE
DCOM- 20100120
LR  - 20220321
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 120
IP  - 1
DP  - 2010 Jan
TI  - Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells 
      to apoptosis induction.
PG  - 142-56
LID - 38942 [pii]
LID - 10.1172/JCI38942 [doi]
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.
FAU - Samudio, Ismael
AU  - Samudio I
AD  - 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.
FAU - Harmancey, Romain
AU  - Harmancey R
FAU - Fiegl, Michael
AU  - Fiegl M
FAU - Kantarjian, Hagop
AU  - Kantarjian H
FAU - Konopleva, Marina
AU  - Konopleva M
FAU - Korchin, Borys
AU  - Korchin B
FAU - Kaluarachchi, Kumar
AU  - Kaluarachchi K
FAU - Bornmann, William
AU  - Bornmann W
FAU - Duvvuri, Seshagiri
AU  - Duvvuri S
FAU - Taegtmeyer, Heinrich
AU  - Taegtmeyer H
FAU - Andreeff, Michael
AU  - Andreeff M
LA  - eng
GR  - P01-CA49639/CA/NCI NIH HHS/United States
GR  - P01-CA16672/CA/NCI NIH HHS/United States
GR  - R01-HL-73162/HL/NHLBI NIH HHS/United States
GR  - P01 CA049639/CA/NCI NIH HHS/United States
GR  - P01 CA055164/CA/NCI NIH HHS/United States
GR  - R01 HL073162/HL/NHLBI NIH HHS/United States
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - P01-CA55164/CA/NCI NIH HHS/United States
GR  - R01 HL061483/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091221
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (ABT-737)
RN  - 0 (BAK1 protein, human)
RN  - 0 (BAX protein, human)
RN  - 0 (Biphenyl Compounds)
RN  - 0 (Fatty Acids)
RN  - 0 (Ion Channels)
RN  - 0 (Mitochondrial Membrane Transport Proteins)
RN  - 0 (Mitochondrial Permeability Transition Pore)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Nitrophenols)
RN  - 0 (Piperazines)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sulfonamides)
RN  - 0 (Uncoupling Protein 2)
RN  - 0 (bcl-2 Homologous Antagonist-Killer Protein)
RN  - 0 (bcl-2-Associated X Protein)
RN  - 04079A1RDZ (Cytarabine)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.3.1.85 (Fatty Acid Synthases)
SB  - IM
MH  - Adenosine Triphosphate/biosynthesis
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Biphenyl Compounds/therapeutic use
MH  - Cell Proliferation
MH  - Cytarabine/therapeutic use
MH  - Fatty Acid Synthases/physiology
MH  - Fatty Acids/*metabolism
MH  - Humans
MH  - Ion Channels/physiology
MH  - Leukemia/*drug therapy/pathology
MH  - Mice
MH  - Mitochondrial Membrane Transport Proteins
MH  - Mitochondrial Permeability Transition Pore
MH  - Mitochondrial Proteins/physiology
MH  - Nitrophenols/therapeutic use
MH  - Oxidation-Reduction
MH  - Piperazines/therapeutic use
MH  - Reactive Oxygen Species
MH  - Sulfonamides/therapeutic use
MH  - Uncoupling Protein 2
MH  - bcl-2 Homologous Antagonist-Killer Protein/chemistry
MH  - bcl-2-Associated X Protein/chemistry
PMC - PMC2799198
EDAT- 2009/12/30 06:00
MHDA- 2010/01/21 06:00
PMCR- 2009/12/21
CRDT- 2009/12/30 06:00
PHST- 2009/02/17 00:00 [received]
PHST- 2009/10/21 00:00 [accepted]
PHST- 2009/12/30 06:00 [entrez]
PHST- 2009/12/30 06:00 [pubmed]
PHST- 2010/01/21 06:00 [medline]
PHST- 2009/12/21 00:00 [pmc-release]
AID - 38942 [pii]
AID - 10.1172/JCI38942 [doi]
PST - ppublish
SO  - J Clin Invest. 2010 Jan;120(1):142-56. doi: 10.1172/JCI38942. Epub 2009 Dec 21.