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

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

Ramon C. Sun Æ Mitali Fadia Æ Jane E. Dahlstrom Æ
Christopher R. Parish Æ Philip G. Board Æ
Anneke C. Blackburn

Received: 17 April 2009 / Accepted: 2 June 2009
Springer Science+Business Media, LLC. 2009
Abstract The glycolytic phenotype is a widespread
phenomenon in solid cancer forms, including breast cancer.
Dichloroacetate (DCA) has recently been proposed as a
novel and relatively non-toxic anti-cancer agent that can
reverse the glycolytic phenotype in cancer cells through the
inhibition of pyruvate dehydrogenase kinase. We have
examined the effect of DCA against breast cancer cells,
including in a highly metastatic in vivo model. The growth
of several breast cancer cell lines was found to be inhibited
by DCA in vitro. Further examination of 13762 MAT rat
mammary adenocarcinoma cells found that reversal of the
glycolytic phenotype by DCA correlated with the inhibition
of proliferation without any increase in cell death. This
was despite a small but significant increase in caspase 3/7
activity, which may sensitize cancer cells to other apoptotic
triggers. In vivo, DCA caused a 58% reduction in the
number of lung metastases observed macroscopically after
injection of 13762 MAT cells into the tail vein of rats
(P = 0.0001, n C 9 per group). These results demonstrate
that DCA has anti-proliferative properties in addition to
pro-apoptotic properties, and can be effective against
highly metastatic disease in vivo, highlighting its potential
for clinical use.
Keywords Dichloroacetate