Bicarbonate and dichloroacetate: Evaluating pH altering therapies in a mouse model for metastatic breast cancer

We posited that safety and efficacy of bicarbonate could be enhanced by dichloroacetate (DCA), a drug that selectively targets tumor cells and reduces extracellular acidity through inhibition of glycolysis. Using our mouse model for metastatic breast cancer (MDA-MB-231), we designed an interventional survival study where tumor bearing mice received bicarbonate, DCA, or DCA-bicarbonate (DB) therapies chronically.Dichloroacetate alone or in combination with bicarbonate did not increase systemic alkalosis in mice. Survival was longest in mice administered bicarbonate-based therapies. Primary tumor re-occurrence after surgeries is associated with survival rates. Although DB therapy did not significantly enhance oral bicarbonate, we did observe reduced pulmonary lesion diameters in this cohort. The DCA monotherapy was not effective in reducing tumor size or metastases or improving survival time. We provide in vitro evidence to suggest this outcome may be a function of hypoxia in the tumor microenvironment.DB combination therapy did not appear to enhance the effect of chronic oral bicarbonate. The anti-tumor effect of DCA may be dependent on the cancer model. Our studies suggest DCA efficacy is unpredictable as a cancer therapy and further studies are necessary to determine the role of this agent in the tumor microenvironment.The extracellular pH of malignant tumors is acidic (pH 6.5-6.9) compared to normal tissue (pH 7.2-7.4) [1-3]. Tumor acidity is thought to play a critical role in chemoresistance [4-6] and promotion of metastatic potential. For example, acidic culture conditions increase filopodia formations and expression of proteolytic enzymes involved in invasion [7]. Other reports have described enhanced invasiveness [8] and increased cathepsin B activity in acid-cultured tumor cells [9]. Acid-mediated metastatic potential has been demonstrated in vivo as well. Tumor cells pre-treated under acidic pH prior to tail vein injection formed a greater number of pulmonar