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Molecular Cancer

, 10:142

First Online: 18 November 2011Received: 03 May 2011Accepted: 18 November 2011

Abstract

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.

KeywordsDichloroacetate breast cancer electron transport chain mitochondria arsenic trioxide List of abbreviationsAPLacute promyeloid leukemia

ATOarsenic trioxide

ATPβATP synthase β subunit

AVannexin V

BAbongkrekic acid

CFSEcarboxyfluorescein succinimidyl ester

CsAcyclosporine A

DCAdichloroacetate

ETCelectron transport chain

H2DCFDA2-, 7-dihydrochlorofluroresceinacetate

JC-15,5-,6,6-tetrachloro-1,1-, 3,3-tetraethylbenzimidazol-carbocyanine iodide

MMPmitochondrial membrane potential

MTPmitochondrial transition pore

NaCNsodium cyanide

PIpropidium iodide

ROSReactive oxygen species

TTFAthenolytrifluoroacetone.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-10-142 contains supplementary material, which is available to authorized users.

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Autor: Ramon C Sun - Philip G Board - Anneke C Blackburn

Fuente: https://link.springer.com/



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