Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC

Abstract

The “Warburg effect,” also termed aerobic glycolysis, describes the increased reliance of cancer cells on glycolysis for ATP production, even in the presence of oxygen. Consequently, there is continued interest in inhibitors of glycolysis as cancer therapeutics. One example is dichloroacetate (DCA), a pyruvate mimetic that stimulates oxidative phosphorylation through inhibition of pyruvate dehydrogenase kinase. In this study, the mechanistic basis for DCA anti‐cancer activity was re‐evaluated in vitro using biochemical, cellular and proteomic approaches. Results demonstrated that DCA is relatively inactive (IC50 ≥ 17 mM, 48 hr), induces apoptosis only at high concentrations (≥25 mM, 48 hr) and is not cancer cell selective. Subsequent 2D‐PAGE proteomic analysis confirmed DCA‐induced growth suppression without apoptosis induction. Furthermore, DCA depolarizes mitochondria and promotes reactive oxygen species (ROS) generation in all cell types. However, DCA was found to have selective activity against rho(0) cells [mitochondrial DNA (mtDNA) deficient] and to synergize with 2‐deoxyglucose in complex IV deficient HCT116 p53(−/−) cells. DCA also synergized in vitro with cisplatin and topotecan, two antineoplastic agents known to damage mitochondrial DNA. These data suggest that in cells “hardwired” to selectively utilize glycolysis for ATP generation (e.g., through mtDNA mutations), the ability of DCA to force oxidative phosphorylation confers selective toxicity. In conclusion, although we provide a mechanism distinct from that reported previously, the ability of DCA to target cell lines with defects in the electron transport chain and to synergize with existing chemotherapeutics supports further preclinical development.

Targeting of two aspects of metabolism in breast cancer treatment

“…21 This dual-targeting strategy is also supported by studies showing DCA to be more effective against cancer cells with mitochondrial defects, such as rho(0) MCF7 cells, 25 mitochondrial ND2 mutant cells 26 and oligomycin-treated HCT116 colon cancer cells. 18 However, the precise mechanism by which DCA enhances cytotoxicity is not always clear.…”

“…Mitochondrial changes may be involved in DCA sensitization of cancer cells toward apoptosis. It has been previously reported that DCA can depolarize the mitochondrial membrane potential (MMP), 7,25 which has been postulated to sensitize cancer cells toward apoptosis. 37 Using JC-1 staining to measure the MMP, it was found that JC-1 red staining decreased from as early as 3 hr post-DCA treatment in T-47D cells (Fig.…”

“…20 DCA has been reported in several studies to be most effective when used in combination with agents that inhibit mitochondrial function. 18,21,25,26 Thus, targeting two aspects of metabolism, using DCA to promote mitochondrial activity and then an anti-mitochondrial agent to simultaneously inhibit mitochondrial function, is a rational approach to cancer therapy.…”

From tumor cell metabolism to tumor immune escape

“…It is believed that by inducing a metabolic change from fermentation to OXPHOS, DCA specifically induces apoptosis in tumor cells. DCA has clinical benefits for the treatment of certain cancer patients (Flavin, 2010,Michelakis et al, 2010, although its use is under debate (Stockwin et al, 2010,Heshe et al, 2011. In view of our results (Charni et al, 2010), it should be interesting to investigate the clinical association of DCA with CTL-mediated immunotherapy because DCAinduced MHC-I expression should facilitate plasma membrane expression of TAAs allowing proper recognition by CTLs.…”

Metabolism targeting therapy of dichloroacetate-loaded electrospun mats on colorectal cancer

“…However, many studies have raised doubts regarding the anti-cancer activity of DCA as a potential metabolism-targeting therapy (Michelakis et al, 2008). The controversy has focused on two issues: inconsistency in anti-cancer activity between in vitro and in vivo studies (Papandreou et al, 2011) and the effectiveness of the DCA administration method (Stockwin et al, 2010;Sun et al, 2010). The opposing findings have mainly arisen from the most studied colorectal cancer model.…”