title: Perturbation of cellular oxidative state induced by dichloroacetate and arsenic trioxide for treatment of acute myeloid leukemia.
abstract: The incidence of acute myeloid leukemia (AML) is rising and the outcome of current therapy, which has not changed significantly in the last 40 years, is suboptimal. Cellular oxidative state is a credible target to selectively eradicate AML cells, because it is a fundamental property of each cell that is sufficiently different between leukemic and normal cells, yet its aberrancy shared among different AML cells. To this end, we tested whether a short-time treatment of AML cells, including cells with FLT3-ITD mutation, with sub-lethal dose of dichloroacetate (DCA) (priming) followed by pharmacologic dose of arsenic trioxide (ATO) in presence of low-dose DCA could produce insurmountable level of oxidative damage that kill AML cells. Using cellular cytotoxicity, apoptotic and metabolic assays with both established AML cell lines and primary AML cells, we found that priming with DCA significantly potentiated the cytotoxicity of ATO in AML cells in a synergistic manner. The combination decreased the mitochondrial membrane potential as well as expression of Mcl-1 and GPx in primary AML cells more than either drug alone. One patient with AML whose disease was refractory to several lines of prior treatments was treated with this combination, and tolerated it well. These data suggest that targeting cellular redox balance in leukemia may provide a therapeutic option for AML patients with relapsed/refractory disease.
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA. Electronic address: aemadi@umm.edu.
authors.forename: Ashkan
authors.initials: A
authors.lastname: Emadi
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA.
authors.forename: Mariola
authors.initials: M
authors.lastname: Sadowska
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Carter-Cooper
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Bhatnagar
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA.
authors.forename: Isabella
authors.initials: I
authors.lastname: van der Merwe
authors.affiliation: Division of Hematologic Malignancies, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Levis
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA.
authors.forename: Rena G
authors.initials: RG
authors.lastname: Lapidus
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003999:Dichloroacetic Acid / Q000627:therapeutic use*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress; D010087:Oxides / Q000627:therapeutic use*
chemical_list: D001152:Arsenicals; D010087:Oxides; D003999:Dichloroacetic Acid; D000077237:Arsenic Trioxide
keywords: AML; Antioxidants; Glycolysis; Mitochondria; Oxidative stress