Evaluation of Long-term Treatment of Children With Congenital Lactic Acidosis With Dichloroacetate

Abstract

Oral dichloroacetate is generally well tolerated in young children with congenital lactic acidosis. Although continued dichloroacetate exposure is associated with evidence of peripheral neuropathy, it cannot be determined whether this is attributable mainly to the drug or to progression of underlying disease.

Cotreatment with dichloroacetate and omeprazole exhibits a synergistic antiproliferative effect on malignant tumors

“…DCA has been used to treat congenital metabolic acidosis and OMP has been used to treat acid-related diseases, both without major side effects (7,8,12,13). The combination of DCA and OMP is expected to reduce the necessary dose of each drug and the accompanying risks.…”

“…This preference for anaerobic respiration is also considered to be the reason for the resistance cancer cells exhibit to anticancer drugs which induce apoptosis via the mitochondrial pathway. Bonnet et al have reported that treating cancer cells with dichloroacetate (DCA), an approved treatment for congenital lactic acidosis, reverses the Warburg effect and inhibits tumor growth (3,4,(6)(7)(8). DCA increases the flux of pyruvate into the mitochondria by inhibiting the pyruvate dehydrogenase kinase and promotes glucose oxidation over glycolysis.…”

“…DCA induces apoptosis via two pathways, one in the mitochondria, where depolarization and superoxide (SOD) production activates mitochondria-dependent apoptosis, and the other at the plasmalemmal level, where activation/upregulation of Kv1.5 channels decreases the (K + )i, activating caspases (6). DCA is a promising anticancer drug due to the convenience of its oral administration, low cost, few side effects and long experience of clinical use (7,8). Although it appeared to be a promising treatment for malignant tumors, its effect is limited in an ongoing report of clinical trials.…”

Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs

“…Thus, selective modulation of the glycolytic phenotype of cancer cells by DCA seems to be a promising approach for an effective and tolerable treatment of cancer [11,12]. For its ability to favour glucose metabolism by aerobic glycolysis, DCA has been used for more than 30 years for the treatment of lactate acidosis and inherited mitochondrial diseases in adults as well as in children [13][14][15]. Though clinical trials in humans with cancer had yet to be performed, DCA was celebrated as the magic bullet against cancer by the public press further stimulating the attraction of DCA for cancer patients.…”

Dichloroacetic Acid (DCA)-Induced Cytotoxicity in Human Breast Cancer Cells Accompanies Changes in Mitochondrial Membrane Permeability and Production of Reactive Oxygen Species

“…Recently, in an in vivo study, DCA has been shown to reduce the growth of lung cancer xenografts and significantly diminish lung metastasis in a rat mammary adenocarcinoma [7]. In addition, the growth of a pancreatic tumor xenograft was also found to be reduced perhaps by reversal of the glycolytic phenotype.…”