Abstract
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.
Highlights
DCA is a promising anticancer drug that antagonizes Warburg effect and exerts potent anticancer effects with promising results in clinical oncology. [1] DCA effectively cured a chemoresistant non-Hodgkin's lymphoma patient after disease progression with rituximab-CHOP chemotherapy. [2] Current pharmacological confirmed DCA well-known mechanism of action through inhibiting pyruvate dehydrogenase kinase (PDK)
Ketolysis is an energy-generating pathway that occurs outside the liver cells
[5] In this article, I prove my novel perspective that DCA antagonizes ketone bodies both structurally (Figure 1) and functionally to target cancer cells energetics through inhibiting ketolysis as a novel evidence-based mechanism of its anticancer effects
Summary
DCA is a promising anticancer drug that antagonizes Warburg effect and exerts potent anticancer effects with promising results in clinical oncology. [1] DCA effectively cured a chemoresistant non-Hodgkin's lymphoma patient after disease progression with rituximab-CHOP chemotherapy. [2] Current pharmacological confirmed DCA well-known mechanism of action through inhibiting pyruvate dehydrogenase kinase (PDK). [2] Current pharmacological confirmed DCA well-known mechanism of action through inhibiting pyruvate dehydrogenase kinase (PDK). [3] This frankly antagonizes cancer phenotype (Warburg effect) and deprives cancer cells of many lactate-based benefits e.g. cancer invasion, metastasis, angiogenesis, chemoresistance and radioresistance. [4] Ketone bodies are three compounds: acetone, acetoacetate and β-hydroxybutyrate. Ketolysis is an energy-generating pathway that occurs outside the liver cells (extrahepatic). [5] In this article, I prove my novel perspective that DCA antagonizes ketone bodies (acetoacetate and β-hydroxybutyrate) both structurally (Figure 1) and functionally to target cancer cells energetics through inhibiting ketolysis as a novel evidence-based mechanism of its anticancer effects It occurs in peripheral tissues. [5] In this article, I prove my novel perspective that DCA antagonizes ketone bodies (acetoacetate and β-hydroxybutyrate) both structurally (Figure 1) and functionally to target cancer cells energetics through inhibiting ketolysis as a novel evidence-based mechanism of its anticancer effects
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call