Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells

Molecular Cancer

Research

Philip G Board¹  Anneke C Blackburn¹  Ramon C Sun² 

[1] Molecular Genetics Group, Department of Translational Biosciences, John Curtin School of Medical Research, Australian National University, P.O. Box 334, Building 131, 0200, Canberra, ACT, AUSTRALIA;Molecular Genetics Group, Department of Translational Biosciences, John Curtin School of Medical Research, Australian National University, P.O. Box 334, Building 131, 0200, Canberra, ACT, AUSTRALIA;Department of Radiation Oncology, Stanford School of Medicine, 94305, Stanford, CA, USA;

关键词: Dichloroacetate;    breast cancer;    electron transport chain;    mitochondria;    arsenic trioxide;   

DOI  :  10.1186/1476-4598-10-142

 received in 2011-05-03, accepted in 2011-11-18,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundCancer 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.MethodsIn 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.ResultsThe 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.ConclusionThis study is the first to demonstrate that targeting two key metabolic hallmarks of cancer is an effective anti-cancer strategy with therapeutic potential.

【 授权许可】

Unknown   
© Sun et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.