Dichloroacetate is an antimetabolite that antagonizes acetate and deprives cancer cells from its benefits: A novel evidence-based medical hypothesis.

Autor: El Sayed SM; Department of Clinical Biochemistry and Molecular Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia; Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Egypt. Electronic address: salahfazara@yahoo.com., Baghdadi H; Department of Clinical Biochemistry and Molecular Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia., Ahmed NS; Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Egypt., Almaramhy HH; Department of Surgery, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia., Mahmoud AA; Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Egypt., El-Sawy SA; Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Egypt., Ayat M; Department of Clinical Biochemistry and Molecular Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia., Elshazley M; Department of Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia; Department of Occupational Diseases and Toxigenomics, Sohag Faculty of Medicine, Sohag University, Egypt., Abdel-Aziz W; Department of Medical Pharmacology, Sohag Faculty of Medicine, Sohag University, Egypt., Abdel-Latif HM; Department of Medical Pharmacology, Sohag Faculty of Medicine, Sohag University, Egypt., Ibrahim W; Department of Medical Pharmacology, Sohag Faculty of Medicine, Sohag University, Egypt., Aboonq MS; Department of Physiology, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.
Jazyk: angličtina
Zdroj: Medical hypotheses [Med Hypotheses] 2019 Jan; Vol. 122, pp. 206-209. Date of Electronic Publication: 2018 Nov 22.
DOI: 10.1016/j.mehy.2018.11.012
Abstrakt: Dichloroacetate (DCA) is a promising safe anticancer drug that cured a patient with chemoresistant non-Hodgkin's lymphoma and treated lactic acidosis effectively. The well-known mechanism of DCA action is through stimulating Krebs cycle (stimulating pyruvate dehydrogenase via inhibiting pyruvate dehydrogenase kinase). This prevents lactate formation (Warburg effect) depriving cancer cells of lactate-based benefits e.g. angiogenesis, chemoresistance and radioresistance. Here, we introduce novel evidence-based hypotheses to explain DCA-induced anticancer effects. On pharmacological and biochemical bases, we hypothesize that DCA is a structural antagonist of acetate competing with it for target enzymes and biological reactions. We hypothesize that DCA exerts its anticancer effects via depriving cancer of acetate benefits. We hypothesize also that acetate is an antidote of DCA capable of treating DCA toxicity. Many reports support our hypotheses. Acetate is vital for cancer cells (tumors depend on acetate) and DCA is structurally similar to acetate. DCA exerts opposite effects to acetate. Acetate caused a decrease in serum potassium, phosphorus and glucose, and an increase in serum lactate, citrate, free fatty acids and ketone bodies (serum acetoacetate and beta-hydroxybutyrate levels). Acetate decreased the proportion of active (dephosphorylated) pyruvate dehydrogenase in perfused rat heart. DCA produced quite opposite effects. Intravenous infusion of acetate produced metabolic alkalemia while DCA caused minimal effects on acid-base status. Acetate is important for cancer cells metabolism and survival as elevated acetate can drive resistance to targeted cancer treatments. Acetate is required for epidermal growth factor receptor vIII mutation in lethal brain tumors. Experimentally, DCA inhibited acetate oxidation in hearts of normal rats and reversed inhibitory effects of acetate on the oxidation of glucose. During presence of DCA with no glucose in heart perfusions with [1-14C]acetate, DCA decreased the specific radioactivity of acetyl CoA and its product citrate. This proves our hypotheses that DCA is an antimetabolite that antagonizes acetate for vital reactions in cancer cells. Acetate may be used as an antidote to combat DCA toxicity.
(Copyright © 2018. Published by Elsevier Ltd.)
Databáze: MEDLINE
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