title: Targeting cancer cells with the natural compound obtusaquinone.
abstract: BACKGROUND
  Tumor cells present high levels of oxidative stress. Cancer therapeutics exploiting such biochemical changes by increasing reactive oxygen species (ROS) production or decreasing intracellular ROS scavengers could provide a powerful treatment strategy.
  
  
  METHODS
  To test the effect of our compound, obtusaquinone (OBT), we used several cell viability assays on seven different glioblastoma (GBM) cell lines and primary cells and on 12 different cell lines representing various cancer types in culture as well as on subcutaneous (n = 7 mice per group) and two intracranial GBM (n = 6-8 mice per group) and breast cancer (n = 6 mice per group) tumor models in vivo. Immunoblotting, immunostaining, flow cytometry, and biochemical assays were used to investigate the OBT mechanism of action. Histopathological analysis (n = 2 mice per group) and blood chemistry (n = 2 mice per group) were used to test for any compound-related toxicity. Statistical tests were two-sided.
  
  
  RESULTS
  OBT induced rapid increase in intracellular ROS levels, downregulation of cellular glutathione levels and increase in its oxidized form, and activation of cellular stress pathways and DNA damage, subsequently leading to apoptosis. Oxidative stress is believed to be the main mechanism through which this compounds targets cancer cells. OBT was well tolerated in mice, slowed tumor growth, and statistically prolonged survival in GBM tumor models. The ratio of median survival in U251 intracranial model in OBT vs control was 1.367 (95% confidence interval [CI] of ratio = 1.031 to 1.367, P = .008). Tumor growth inhibition was also observed in a mouse breast cancer model (average tumor volume per mouse, OBT vs control: 36.3 vs 200.4mm(3), difference = 164.1mm(3), 95% CI =72.6 to 255.6mm(3), P = .005).
  
  
  CONCLUSIONS
  Given its properties and efficacy in cancer killing, our results suggest that OBT is a promising cancer therapeutic.
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. badr.christian@mgh.harvard.edu
authors.forename: Christian E
authors.initials: CE
authors.lastname: Badr
authors.forename: Stephanie
authors.initials: S
authors.lastname: Van Hoppe
authors.forename: Hawasatu
authors.initials: H
authors.lastname: Dumbuya
authors.forename: Lee-Ann
authors.initials: LA
authors.lastname: Tjon-Kon-Fat
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology*; D003512:Cyclohexanones / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D015536:Down-Regulation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002934:Cinnamates; D003512:Cyclohexanones; D017382:Reactive Oxygen Species; C039277:obtusaquinone; D005978:Glutathione