Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo

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Reversal of the glycolytic phenotype by dichloroacetate inhibitsmetastatic breast cancer cell growth in vitro and in vivo
Ramon C. Sun Æ Mitali Fadia Æ Jane E. Dahlstrom ÆChristopher R. Parish Æ Philip G. Board ÆAnneke C. Blackburn
Received: 17 April 2009 / Accepted: 2 June 2009 Springer Science+Business Media, LLC. 2009Abstract The glycolytic phenotype is a widespreadphenomenon in solid cancer forms, including breast cancer.Dichloroacetate (DCA) has recently been proposed as anovel and relatively non-toxic anti-cancer agent that canreverse the glycolytic phenotype in cancer cells through theinhibition of pyruvate dehydrogenase kinase. We haveexamined the effect of DCA against breast cancer cells,including in a highly metastatic in vivo model. The growthof several breast cancer cell lines was found to be inhibitedby DCA in vitro. Further examination of 13762 MAT ratmammary adenocarcinoma cells found that reversal of theglycolytic phenotype by DCA correlated with the inhibitionof proliferation without any increase in cell death. Thiswas despite a small but significant increase in caspase 3/7activity, which may sensitize cancer cells to other apoptotictriggers. In vivo, DCA caused a 58% reduction in thenumber of lung metastases observed macroscopically afterinjection of 13762 MAT cells into the tail vein of rats(P = 0.0001, n C 9 per group). These results demonstratethat DCA has anti-proliferative properties in addition topro-apoptotic properties, and can be effective againsthighly metastatic disease in vivo, highlighting its potentialfor clinical use.Keywords Dichloroacetate