Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS

Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs

“…Tolerable DCA dosages of 25 mg/kg/d given twice daily, which were clinically applied for the treatment of mitochondrial disorders, resulted in peak plasma concentrations of 100-250 µmol/L after the first dose and 200-550 µmol/L after 6 month of therapy [23]. Plasma concentrations of about 1 mmol/L were observed after the first application of 50 mg/kg DCA as well as after chronic exposure to 25 mg/kg DCA [15,24]. Higher plasma concentrations would require higher dosages, whose tolerability has not been evaluated so far.…”

“…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.…”

Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer

“…This is also true for DCA metabolites (which do not have any biologic effect, at least on PDH). For example, the serum DCA levels after 5 years of continued treatment with oral DCA at 25 mg kg À1 are only slightly increased compared with the levels after the first several doses (and remain in the range of approximately 100 mg ml À1 ) (Mori et al, 2004). The effects on lactate levels are sustained and persist after the DCA levels decrease, because the inhibition of PDK is not immediately reversible; DCA 'locks' PDK in a sustained inactive state.…”

Development of a dichloroacetic acid‐hemoglobin conjugate as a potential targeted anti‐cancer therapeutic

“…Fortunately, normal cells undergo normal levels of TCA cycle activity, and therefore will not be influenced by DCA treatment (Bonnet et al, 2007;Madhok et al, 2010). However, clinical trials showed that patients directly treated with DCA suffer from peripheral neuropathy (Kaufmann et al, 2006) and central nervous system dysfunction (Mori et al, 2004), suggesting that DCA possesses side-effects that are focused on the neural system. Hence targeted delivery of DCA towards cancerous cells could eliminate/attenuate the severity of these adverse sideeffects.…”