Dichloroacetate Enhances Adriamycin-Induced Hepatoma Cell Toxicity In Vitro and In Vivo by Increasing Reactive Oxygen Species Levels

Abstract

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.

Restoration of mitochondria function as a target for cancer therapy

“…Furthermore, a case study reported that DCA in combination with omeprazole (a proton pump inhibitor) and/or tamoxifen exhibited synergistic antiproliferative effects on malignant tumors [92]. DCA enhances adriamycin-induced hepatoma cell killing by inducing ROS levels in vitro as well as in vivo [93]. Interestingly, enhancement in sensitization to various anticancer agents in the presence of DCA has been attributed to the modulation of tumor microenvironment, which requires reprogramming of glucose metabolism, perturbations in pH levels, induction of ROS, and modulation of survival pathways [82].…”

Complex I inhibition augments dichloroacetate cytotoxicity through enhancing oxidative stress in VM-M3 glioblastoma cells

“…DCA potentiates the cytotoxicity of several chemotherapies and reverses HIF-mediated resistance to bevacizumab in a model of glioblastoma [11–16]. Moreover, DCA promoted stable disease in patients with malignant brain tumors in a Phase I trial [22].…”

Targeting glucose metabolism in cancer: a new class of agents for loco-regional and systemic therapy of liver cancer and beyond?

“…found that DCA was able to overcome sorafenib-resistance in a subcutaneous xenograft mouse model with sorafenib-resistant HCC cells [47]. Regarding oral combination therapy, enhanced cytotoxic effects were recently reported for adriamycin with simultaneously administered DCA in hepatoma cells in vitro as well as in subcutaneous mouse xenografts [48].…”