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A unique bioenergetic feature of cancer, aerobic glycolysis is considered an attractive therapeutic target for cancer therapy. Recently, dichloroacetate (DCA), a small-molecule metabolic modulator, was shown to reverse the glycolytic phenotype, induce reactive oxygen species (ROS) generation, and trigger apoptosis in various tumor cells. In this work, the capacity of DCA to enhance Adriamycin (ADM) efficacy in hepatoma cells by modulating glucose metabolism and redox status was evaluated. Two human hepatoma (HCC-LM3 and SMMC-7721) and a normal liver (LO2) cell lines were treated with DCA or ADM alone, or in combination. Exposure of hepatoma cells to DCA/ADM combination resulted in significantly decreased cell viability and increased percentage of apoptotic cells as well as intracellular ROS levels, in comparison with treatment with DCA or ADM alone. However, simultaneous treatment with the thiol antioxidant N-acetylcysteine (NAC, 10 mmol/L) reduced the elevated ROS levels and protected hepatoma cells from the cytotoxic effects of DCA/ADM combination. L-buthionine-[S,R]-sulfoximine, an inhibitor of glutathione synthesis, enhanced hepatoma cell sensitivity to DCA/ADM combination. Interestingly, treatment with DCA/ADM combination did not significantly increase cytotoxicity in normal hepatocytes in comparison with the drugs administered individually. Finally, DCA reduced tumor growth and enhanced ADM efficacy on HCC-LM3 hepatoma in mice. Overall, our data suggest that DCA enhances ADM cytotoxicity in hepatoma cells by increasing intracellular ROS levels and provide a strong biochemical rationale for the use of DCA in combination with ADM for treatment of hepatoma. [ABSTRACT FROM AUTHOR]

Solid tumors grow faster and need more glucose than normal tissue; however, due to poor angiogenesis and excessive growth, tumors remote from blood vessels are always under glucose starvation. Even so, cancer cells remain alive in vivo. Thus, making cancer cells sensitive to glucose depletion may potentially provide an effective strategy for cancer intervention. Tumors that obtain sufficient glucose generate a large amount of lactate. Therefore, we proposed that lactate, a tumor microenvironment factor, may allow cancer cells to develop resistance to glucose starvation-induced death. We cultured cancer cells in no-glucose medium and added lactate to the medium. During the experiment, lactate helped cancer cells to escape from glucose starvation-induced cell death, without using lactate as an energy substrate, resulting in activation of Akt through PI3K. Akt activation plays a central role in cell growth through the activation of mammalian target of rapamycin (mTOR). Alteration of the PI3K/Akt/mTOR signaling pathway by inhibiting apoptosis induced specific upregulation of B-cell lymphoma 2 (Bcl-2) through translational control. In conclusion, this study showed that lactate rescues cancer cells from glucose starvation-induced cell death through regulation of the PI3K/Akt/mTOR/Bcl-2 signaling pathway. These data suggest that lactate is an important determinant of the sensitivity of tumors to glucose starvation, and reducing lactate or inhibiting the PI3K/Akt/mTOR/Bcl-2 signaling pathway may influence the response of cancers to glucose starvation.