Dichloroacetate is Promising for Treating Hematological Malignancy through Inhibiting Ketone Bodies Oxidation: towards Better Understanding of Its Anticancer Mechanisms

摘要

Dichloroacetate (DCA) is a promising anticancer drug that exerts potent anticancer effects in many clinical oncology studies. On biochemical and pharmacological bases, this article aims at gaining a better understanding of DCA anticancer effects. Ketone bodies oxidation (ketolysis) is an important source of energy to many cancer cells. Here, it is proved that DCA antagonizes acetoacetate and targets cancer cells' energetics through inhibiting ketolysis as novel evidence-based anticancer mechanisms. DCA was reported to inhibit oxidation of both ketone bodies (acetoacetate and β-hydroxybutyrate) in addition to palmitate. Acetoacetate diverted pyruvate metabolism from pyruvate dehydrogenase (PDH) to pyruvate carboxylation while DCA increased the oxidation of glucose through PDH. This suggests an antagonism between DCA and ketone bodies. Moreover, DCA was reported to inhibit β-hydroxybutyrate uptake by the extra-splanchnic tissues and decrease the clearance of ketone bodies. That may be explained by structural antagonism between DCA and ketone bodies leading to a competitive uptake at target tissues i.e. DCA may competitively antagonize ketone bodies. In a previous study, DCA infusion in starved rats caused a significant decrease in blood glucose, plasma insulin, blood lactate and pyruvate concentrations but significantly increased concentrations of ketone bodies (β-hydroxybutyrate and acetoacetate) (Blackshear et al., 1974). Based on that, DCA inhibits ketone bodies utilization for energy production. In conclusion, DCA enhances anticancer immunity, targets anaerobic cancer cell populations (via targeting Warburg effect) and targets aerobic cancer cell populations through targeting mitochondrial energy generating pathways e.g. ketolysis.