Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications

Abstract

An extensive body of literature describes anticancer property of dichloroacetate (DCA), but its effective clinical administration in cancer therapy is still limited to clinical trials. The occurrence of side effects such as neurotoxicity as well as the suspicion of DCA carcinogenicity still restricts the clinical use of DCA. However, in the last years, the number of reports supporting DCA employment against cancer increased also because of the great interest in targeting metabolism of tumour cells. Dissecting DCA mechanism of action helped to understand the bases of its selective efficacy against cancer cells. A successful coadministration of DCA with conventional chemotherapy, radiotherapy, other drugs, or natural compounds has been tested in several cancer models. New drug delivery systems and multiaction compounds containing DCA and other drugs seem to ameliorate bioavailability and appear more efficient thanks to a synergistic action of multiple agents. The spread of reports supporting the efficiency of DCA in cancer therapy has prompted additional studies that let to find other potential molecular targets of DCA. Interestingly, DCA could significantly affect cancer stem cell fraction and contribute to cancer eradication. Collectively, these findings provide a strong rationale towards novel clinical translational studies of DCA in cancer therapy.

The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment

“…Zhou et al [ 318 ], showed that combining of chemotherapy, together with inhibition of glycolysis by 3-bromopyruvate, effectively eradicates GCSCs in their hypoxic niches, where they exhibit resistant to mono-therapy by chemotherapeutic agents, and tend to reside in hypoxia and perform glycolysis for ATP generation in order to maintain their stemness and highly tumor forming capacity. In addition, in several cancer models, inhibition of PDKII by dichloroacetate has been demonstrated to reverse the metabolic shift from glycolysis to OXPHOS, increase ROS and promote apoptosis in CSCs and tumor cells [ 319 , 320 ].…”

Inhibition of pyruvate dehydrogenase kinase‑1 by dicoumarol enhances the sensitivity of hepatocellular carcinoma cells to oxaliplatin via metabolic reprogramming

“…The classic inhibitor of PDK1 is sodium dichloroacetate (DCA); however, its clinical trials has been terminated due to its severe side-effects ( 38 - 40 ). However, when used in co-treatment with the chemotherapeutic drug, paclitaxel (PTX), DCA markedly decreased cell autophagy, enhanced apoptosis and inhibited the proliferation of A549 and H1975 cells ( 41 ).…”

Inhibition of pyruvate dehydrogenase kinase redirects NSCLC cell metabolism and counteracts development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors

“…The bioenergetic difference between cancer and normal cells may offer selective therapeutic targets, as dependence on glycolysis and lactic fermentation is only found in skeletal muscle cells during strenuous exercise. Side effects from continuous use of DCA has been few, but include reversible peripheral neuropathy [70]. However this effect seems to be limited to patients with mitochondrial diseases [93].…”

“…Inhibitory phosphorylation of PDH by the PDKs leads to increased ux of pyruvate to lactate at the expense of mitochondrial pyruvate oxidation [67,68]. [69,70]. Dichloroacetate (DCA) is a natural occurring pyruvate analog, which acts as a PDK inhibitor, inducing increased mitochondrial pyruvate oxidation [69,70].…”

“…[69,70]. Dichloroacetate (DCA) is a natural occurring pyruvate analog, which acts as a PDK inhibitor, inducing increased mitochondrial pyruvate oxidation [69,70]. By inhibiting PDK, PDH is maintained in a catalytically active state, and the pyruvate pool available from glycolysis is decreased, thus production of lactate and acidi cation of the microenvironment is limited [71].…”