Reversal of the glycolytic phenotype with dichloroacetate in a mouse mammary adenocarcinoma model

Abstract

Dichloroacetate (DCA) has recently been proposed as a novel non-toxic anticancer agent that can reverse the glycolytic phenotype in cancer cells through the inhibition of pyruvate dehydrogenase kinase. Aims and Methods Three mouse cancer cell lines (V14, 4T1 and B16) were used to examine the histological changes caused by DCA in vivo. V14 or 4T1 mammary adenocarcinoma cells were injected subcutaneously and B16 melanoma cells were injected intravenously. Mice were treated with 0.5–2.0 g/L DCA in the drinking water. Results Growth of established V14 tumours was halted by DCA treatment (28% reduction in size, 1.5 g/L for 9 days, n = 8 per group, p = 0.08). Treatment from the day of cell injection resulted in fewer tumours being established (5/8 sites in treated mice vs 16/16 untreated, p = 0.03) and complete regression of one tumour. Histological assessment found DCA treatment resulted in increased tumour-infiltrating lymphocytes (TILs) but no change in mitotic rate, fibrosis or necrosis. Tumours from the 4T1 or B16 cell lines showed no growth inhibition and no evidence of TILs, correlating with a lack of sensitivity to growth inhibition in vitro. Conclusions In V14 tumours DCA appears to prevent or delay breast cancer formation either through growth inhibition or enhanced immune function.