title: Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death.
abstract: BACKGROUND
  Recent research has revealed that targeting mitochondrial bioenergetic metabolism is a promising chemotherapeutic strategy. Key to successful implementation of this chemotherapeutic strategy is the use of new and improved mitochondria-targeted cationic agents that selectively inhibit energy metabolism in breast cancer cells, while exerting little or no long-term cytotoxic effect in normal cells.
  
  
  METHODS
  In this study, we investigated the cytotoxicity and alterations in bioenergetic metabolism induced by mitochondria-targeted vitamin E analog (Mito-chromanol, Mito-ChM) and its acetylated ester analog (Mito-ChMAc). Assays of cell death, colony formation, mitochondrial bioenergetic function, intracellular ATP levels, intracellular and tissue concentrations of tested compounds, and in vivo tumor growth were performed.
  
  
  RESULTS
  Both Mito-ChM and Mito-ChMAc selectively depleted intracellular ATP and caused prolonged inhibition of ATP-linked oxygen consumption rate in breast cancer cells, but not in non-cancerous cells. These effects were significantly augmented by inhibition of glycolysis. Mito-ChM and Mito-ChMAc exhibited anti-proliferative effects and cytotoxicity in several breast cancer cells with different genetic background. Furthermore, Mito-ChM selectively accumulated in tumor tissue and inhibited tumor growth in a xenograft model of human breast cancer.
  
  
  CONCLUSIONS
  We conclude that mitochondria-targeted small molecular weight chromanols exhibit selective anti-proliferative effects and cytotoxicity in multiple breast cancer cells, and that esterification of the hydroxyl group in mito-chromanols is not a critical requirement for its anti-proliferative and cytotoxic effect.
authors.affiliation: Free Radical Research Center and Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.forename: Jacek
authors.initials: J
authors.lastname: Zielonka
authors.forename: Donna M
authors.initials: DM
authors.lastname: McAllister
authors.forename: A Craig
authors.initials: AC
authors.lastname: Mackinnon
authors.forename: Joy
authors.initials: J
authors.lastname: Joseph
authors.forename: Michael B
authors.initials: MB
authors.lastname: Dwinell
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002839:Chromans; D014810:Vitamin E; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman