Abstract #2071: New drug combinations to target the Warburg effect in cancer therapy

A hyperpolarised mitochondrial membrane potential otherwise called the Warburg effect is one of the most common hallmarks of cancer. Although many theories have been proposed, the reason behind this unusual phenotype still remains controversial. We examined the effect of arsenic trioxide (ATO), an anti-cancer drug and dichloroacetate (DCA), a Krebs cycle activator on cancer cells. Although both compounds have been shown to depolarize the mitochondrial membrane potential in cancer cells, our data show that this effect is achieved by different mechanisms. T47D human breast cancer cells were used to assess the effect of ATO and DCA. Both drugs showed good cytostatic effects with 5\#956;M ATO and 5mM DCA inhibiting cell proliferation. While 20\#956;M ATO induced necrosis, no apoptosis or necrosis was observed after DCA treatment. JC-1 staining showed that ATO (5µM for 12 hours) depolarised the mitochondrial membrane potential in 59.3±4% of cells, reduced intracellular ATP levels by 14±4% and inhibited intracellular ROS production by 38±0.7%. These data indicate that ATO is an electron transport chain inhibitor. In contrast, while DCA (5mM for 12 hours) depolarised the mitochondrial potential by 33.8±0.3%, it increased both intracellular ROS and ATP levels by 27.3±3.9% and 8±1% respectively. This indicates that compared to ATO, DCA has a different mode of action inside the mitochondria. These data suggested that targeting both mechanisms with ATO and DCA could be an effective anti-cancer strategy and we confirmed that ATO and DCA have a synergistic effect on proliferation and necrosis of T47D cells. The separate actions of ATO and DCA have allowed us to propose a new model to explain the hyperpolarised mitochondria membrane potential of the Warburg effect in tumour cells.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2071.