title: Inhibition of mitochondrial respiration and rapid depletion of mitochondrial glutathione by β-phenethyl isothiocyanate: mechanisms for anti-leukemia activity.
abstract: OBJECTIVE
  β-Phenethyl isothiocyanate (PEITC) is a natural product with potent anticancer activity against human leukemia cells including drug-resistant primary leukemia cells from patients. This study aimed at investigating the key mechanisms that contribute to the potent anti-leukemia activity of PEITC and at evaluating its therapeutic potential.
  
  
  RESULTS
  Our study showed that PEITC caused a rapid depletion of mitochondrial glutathione (GSH) and a significant elevation of reactive oxygen species (ROS) and nitric oxide, and induced a disruption of the mitochondrial electron transport complex I manifested by an early degradation of NADH dehydrogenase Fe-S protein-3 and a significant suppression of mitochondrial respiration. Using biochemical and pharmacological approaches, we further showed that inhibition of mitochondrial respiration alone by rotenone caused only a moderate cytotoxicity in leukemia cells, whereas a combination of respiratory inhibition and an ROS-generating agent exhibited a synergistic effect against leukemia and lymphoma cells.
  
  
  CONCLUSIONS
  Although PEITC is a reactive compound and might have multiple mechanisms of action, we showed that a rapid depletion of GSH and inhibition of mitochondrial respiration are two important early events that induced synergistic cytotoxicity in leukemia cells. These findings not only suggest that PEITC is a promising compound for potential use in leukemia treatment, but also provide a basis for developing new therapeutic strategies to effectively kill leukemia cells by using a novel combination to modulate ROS and inhibit mitochondrial respiration.
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Yumin
authors.initials: Y
authors.lastname: Hu
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D007938:Leukemia / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008954:Models, Biological; D009245:NADH Dehydrogenase / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D019328:Buthionine Sulfoximine; C058305:phenethyl isothiocyanate; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C472512:NDUFS3 protein, human; D005978:Glutathione