title: Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells.
abstract: BACKGROUND
  Cancer cells have a different metabolic profile compared to normal cells. The Warburg effect (increased aerobic glycolysis) and glutaminolysis (increased mitochondrial activity from glutamine catabolism) are well known hallmarks of cancer and are accompanied by increased lactate production, hyperpolarized mitochondrial membrane and increased production of reactive oxygen species.
  
  
  METHODS
  In this study we target the Warburg effect with dichloroacetate (DCA) and the increased mitochondrial activity of glutaminolysis with arsenic trioxide (ATO) in breast cancer cells, measuring cell proliferation, cell death and mitochondrial characteristics.
  
  
  RESULTS
  The combination of DCA and ATO was more effective at inhibiting cell proliferation and inducing cell death than either drug alone. We examined the effect of these treatments on mitochondrial membrane potential, reactive oxygen species production and ATP levels and have identified new molecular mechanisms within the mitochondria for both ATO and DCA: ATO reduces mitochondrial function through the inhibition of cytochrome C oxidase (complex IV of the electron transport chain) while DCA up-regulates ATP synthase β subunit expression. The potentiation of ATO cytotoxicity by DCA is correlated with strong suppression of the expression of c-Myc and HIF-1α, and decreased expression of the survival protein Bcl-2.
  
  
  CONCLUSIONS
  This study is the first to demonstrate that targeting two key metabolic hallmarks of cancer is an effective anti-cancer strategy with therapeutic potential.
authors.affiliation: Department of Translational Biosciences, Australian National University, Canberra ACT 0200, Australia.
authors.forename: Ramon C
authors.initials: RC
authors.lastname: Sun
authors.forename: Philip G
authors.initials: PG
authors.lastname: Board
authors.forename: Anneke C
authors.initials: AC
authors.lastname: Blackburn
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D003999:Dichloroacetic Acid; D000077237:Arsenic Trioxide
references.citation: Life Sci. 2002 Mar 29;70(19):2253-69
references.pmid: 12005185
references.citation: J Neurochem. 2002 Mar;80(5):780-7
references.pmid: 11948241
references.citation: Acta Oncol. 2007;46(4):557-61
references.pmid: 17497326
references.citation: Carcinogenesis. 2010 Apr;31(4):567-76
references.pmid: 20080835
references.citation: World J Gastroenterol. 2004 Dec 15;10(24):3677-9
references.pmid: 15534931
references.citation: Cancer Treat Rev. 2007 Oct;33(6):542-64
references.pmid: 17624680
references.citation: Cancer Res. 2006 Sep 15;66(18):8927-30
references.pmid: 16982728
references.citation: Cancer Sci. 2003 Nov;94(11):1010-4
references.pmid: 14611680
references.citation: Int J Cancer. 2011 Mar 1;128(5):1001-8
references.pmid: 20957634
references.citation: Blood. 2000 Feb 1;95(3):1014-22
references.pmid: 10648417
references.citation: Blood. 1996 Aug 1;88(3):1052-61
references.pmid: 8704214
references.citation: Cell Signal. 1999 Jan;11(1):1-14
references.pmid: 10206339
references.citation: Oncogene. 2004 Feb 12;23(6):1239-47
references.pmid: 14647451
references.citation: Cancer Cell. 2007 Jan;11(1):37-51
references.pmid: 17222789
references.citation: Chem Res Toxicol. 2003 Mar;16(3):409-14
references.pmid: 12641442
references.citation: Gynecol Oncol. 2008 Jun;109(3):394-402
references.pmid: 18423823
references.citation: Oncologist. 2001;6 Suppl 2:1-2
references.pmid: 11331433
references.citation: Blood. 1997 May 1;89(9):3354-60
references.pmid: 9129042
references.citation: Biochem J. 2004 Feb 15;378(Pt 1):17-20
references.pmid: 14683524
references.citation: J Cell Sci. 2007 Mar 1;120(Pt 5):895-907
references.pmid: 17298978
references.citation: J Cell Physiol. 2002 Jul;192(1):1-15
references.pmid: 12115731
references.citation: Mol Cell Biochem. 2005 Sep;277(1-2):33-42
references.pmid: 16132712
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50
references.pmid: 18032601
references.citation: Blood. 2010 Nov 11;116(19):3751-7
references.pmid: 20705755
references.citation: Cancer Res. 2001 Jul 15;61(14):5432-40
references.pmid: 11454688
references.citation: Met Based Drugs. 2008;2008:260146
references.pmid: 18431449
references.citation: Drug Resist Updat. 2004 Apr;7(2):97-110
references.pmid: 15158766
references.citation: Leukemia. 2000 Feb;14(2):262-70
references.pmid: 10673743
references.citation: Breast Cancer Res Treat. 2010 Feb;120(1):253-60
references.pmid: 19543830
references.citation: Blood. 2008 Mar 1;111(5):2505-15
references.pmid: 18299451
references.citation: Biochem Pharmacol. 2009 Apr 15;77(8):1358-63
references.pmid: 19426674
references.citation: Cancer. 2005 Oct 15;104(8):1687-92
references.pmid: 16130126
references.citation: Free Radic Res. 1999 Oct;31(4):273-300
references.pmid: 10517533
references.citation: Science. 1997 Feb 21;275(5303):1129-32
references.pmid: 9027314
references.citation: Free Radic Biol Med. 2001 Dec 1;31(11):1287-312
references.pmid: 11728801
references.citation: Cancer Res. 2003 May 1;63(9):2103-8
references.pmid: 12727826
references.citation: Blood Rev. 2010 Jul-Sep;24(4-5):191-9
references.pmid: 20471733
references.citation: Science. 1996 May 24;272(5265):1136-44
references.pmid: 8638158
references.citation: Semin Cancer Biol. 2006 Aug;16(4):253-64
references.pmid: 16904903
references.citation: Prostate. 2008 Aug 1;68(11):1223-31
references.pmid: 18465755
references.citation: Ai Zheng. 2006 Jan;25(1):17-21
references.pmid: 16405743
references.citation: Biochim Biophys Acta. 1998 Aug 10;1366(1-2):151-65
references.pmid: 9714783
references.citation: Sci Transl Med. 2010 May 12;2(31):31ra34
references.pmid: 20463368
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12288-93
references.pmid: 17640917
references.citation: PLoS One. 2009 Sep 15;4(9):e7033
references.pmid: 19753307
references.citation: Leuk Lymphoma. 2008 Oct;49(10):1846-51
references.pmid: 18949607
references.citation: Science. 1998 Sep 25;281(5385):2027-31
references.pmid: 9748162
references.citation: Semin Cancer Biol. 2009 Feb;19(1):12-6
references.pmid: 19114105
references.citation: Exp Cell Res. 1999 Jun 15;249(2):413-21
references.pmid: 10366441
references.citation: Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6658-63
references.pmid: 9192621
references.citation: Clin Cancer Res. 2010 Jun 1;16(11):3019-27
references.pmid: 20501625
references.citation: Int J Cancer. 2010 Dec 1;127(11):2510-9
references.pmid: 20533281
references.citation: Anal Biochem. 1993 Oct;214(1):45-9
references.pmid: 8250253