title: AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress.
abstract: Mitochondrial respiration is a crucial component of cellular metabolism that can become dysregulated in cancer. Compared with normal hematopoietic cells, acute myeloid leukemia (AML) cells and patient samples have higher mitochondrial mass, without a concomitant increase in respiratory chain complex activity. Hence these cells have a lower spare reserve capacity in the respiratory chain and are more susceptible to oxidative stress. We therefore tested the effects of increasing the electron flux through the respiratory chain as a strategy to induce oxidative stress and cell death preferentially in AML cells. Treatment with the fatty acid palmitate induced oxidative stress and cell death in AML cells, and it suppressed tumor burden in leukemic cell lines and primary patient sample xenografts in the absence of overt toxicity to normal cells and organs. These data highlight a unique metabolic vulnerability in AML, and identify a new therapeutic strategy that targets abnormal oxidative metabolism in this malignancy.
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Shrivani
authors: S
authors: Sriskanthadevan
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Danny V
authors: DV
authors: Jeyaraju
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Timothy E
authors: TE
authors: Chung
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Swayam
authors: S
authors: Prabha
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Wei
authors: W
authors: Xu
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Marko
authors: M
authors: Skrtic
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Bozhena
authors: B
authors: Jhas
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Rose
authors: R
authors: Hurren
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Marcela
authors: M
authors: Gronda
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Xiaoming
authors: X
authors: Wang
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Yulia
authors: Y
authors: Jitkova
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Mahadeo A
authors: MA
authors: Sukhai
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Feng-Hsu
authors: FH
authors: Lin
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Neil
authors: N
authors: Maclean
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Rob
authors: R
authors: Laister
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Carolyn A
authors: CA
authors: Goard
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Peter J
authors: PJ
authors: Mullen
authors: Division of Stem Cell and Developmental Biology, Campbell Family Institute for Cancer Research/Ontario Cancer Institute, Toronto, ON, Canada; and.
authors: Stephanie
authors: S
authors: Xie
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Linda Z
authors: LZ
authors: Penn
authors: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors: Ian M
authors: IM
authors: Rogers
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada; Division of Stem Cell and Developmental Biology, Campbell Family Institute for Cancer Research/Ontario Cancer Institute, Toronto, ON, Canada; and.
authors: John E
authors: JE
authors: Dick
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Mark D
authors: MD
authors: Minden
authors: Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada;
authors: Aaron D
authors: AD
authors: Schimmer
mesh_terms: D016923:Cell Death; D019069:Cell Respiration; D004579:Electron Transport; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D053142:Mitochondrial Size; D018384:Oxidative Stress / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D017382:Reactive Oxygen Species
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