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

Abstract

Dichloroacetate (DCA) has recently been proposed as a novel and relatively non-toxic anticancer agent that can reverse the glycolytic phenotype in cancer cells through the inhibition of pyruvate dehydrogenase kinase. Over 90% of all tumours show an increased glycolysis and this response could contribute to tumour progression, metastasis and resistance to various chemotherapy agents. Reversing the glycolytic phenotype could potentially slow down tumour growth, induce apoptosis and delay metastasis and is therefore a potential anti-cancer strategy. Aims and Methods Rat breast adenocarcinoma cell lines were used to examine the effect of DCA both in vitroand in vivo. Results The growth of several breast cancer cell lines (MCF-7, T47D, 13762 MAT and V14 cells) was found to be inhibited by DCA in vitro.Further examination of 13762 MAT breast 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 sensitise 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>9 per group). The lesions in the DCA treated rats developed less tumoral necrosis, had a higher mitotic count and a greater lymphocytic infiltration than the control group. Conclusion These results demonstrate the anti-cancer potential of DCA and the reversing the glycolytic phenotype.