Prokhorova I. The combined use of metabolic modifiers as a way to improve the effectiveness of sodium dichloroacetate regarding malignant tumors (experimental study)

Dissertation is aimed at analysis of antitumor action of sodium dichloroacetate (DCA) against tumors of various genesis, ascertainment of mechanisms of realization of this effect and the development of the approaches for increasing its efficiency due to combined use of DCA with such inhibitors of cancer cell energetic metabolism as hypoxia, the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) and tumor angiogenesis inhibitor aconitine containing agent BC1. It was shown that in contrast to normoxic conditions under which DCA doesn’t affect lifetime of rats with glioma C6, DCA treatment of rats with glioma under hypoxic conditions leads to prolongation of animals' lifetime on 22% (p <0,05). As it was revealed in vitro such increase of DCA efficacy against glioma C6 may result from an ability of hypoxia to elevate the cytotoxic activity of DCA the level of which under normoxia are extremely low. The inclusion of 2-DG in the scheme of DCA treatment causes significant anti-tumor effect against high-angiogenic variant of Lewis lung carcinoma, which was absent when the mice were treated with DCA alone. A significant increase of DCA anti-tumor efficiency regarding Ehrlich carcinoma occurred in its combined use with an inhibitor of tumor angiogenesis BC1. For the first time it was revealed that considerable stimulation of ROS production by tumor-associated CD14+ cells induced by DCA (in either monotherapy or combined with other inhibitors of cancer cell energy metabolism) makes significant contribution to DCA anti-tumor efficacy.