二氯乙酸是一种代谢拮抗物，可拮抗乙酸盐并使癌细胞失去其益处：一种新的基于证据的医学假说。

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

机构信息

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.

Department of Clinical Biochemistry and Molecular Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.

出版信息

Med Hypotheses. 2019 Jan;122:206-209. doi: 10.1016/j.mehy.2018.11.012. Epub 2018 Nov 22.

DOI:10.1016/j.mehy.2018.11.012

PMID:30593413

Abstract

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.

摘要

二氯乙酸 (DCA) 是一种有前途的安全抗癌药物，已治愈一名化疗耐药性非霍奇金淋巴瘤患者，并有效治疗乳酸酸中毒。DCA 作用的著名机制是通过刺激克雷布斯循环（通过抑制丙酮酸脱氢酶激酶来刺激丙酮酸脱氢酶）。这阻止了乳酸的形成（Warburg 效应），剥夺了癌细胞基于乳酸的益处，例如血管生成、化疗耐药性和放射耐药性。在这里，我们引入新的基于证据的假设来解释 DCA 诱导的抗癌作用。基于药理学和生物化学基础，我们假设 DCA 是乙酸的结构拮抗剂，与乙酸竞争靶酶和生物反应。我们假设 DCA 通过剥夺癌症细胞的乙酸益处来发挥其抗癌作用。我们还假设乙酸是 DCA 的解毒剂，能够治疗 DCA 毒性。许多报告支持我们的假设。乙酸对癌细胞至关重要（肿瘤依赖于乙酸），DCA 在结构上与乙酸相似。DCA 产生与乙酸相反的作用。乙酸导致血清钾、磷和葡萄糖减少，血清乳酸、柠檬酸、游离脂肪酸和酮体（血清乙酰乙酸和β-羟丁酸水平）增加。乙酸降低了灌注大鼠心脏中活性（去磷酸化）丙酮酸脱氢酶的比例。DCA 产生了相当相反的效果。静脉输注乙酸可产生代谢性碱中毒，而 DCA 对酸碱状态的影响最小。乙酸对癌细胞代谢和存活很重要，因为升高的乙酸可导致对靶向癌症治疗的耐药性。乙酸是表皮生长因子受体 vIII 突变在致命脑肿瘤中的必需物质。实验中，DCA 抑制了正常大鼠心脏中乙酸的氧化，并逆转了乙酸对葡萄糖氧化的抑制作用。在心脏灌注中存在 DCA 且没有葡萄糖时，用 [1-14C]乙酸，DCA 降低了乙酰辅酶 A 的比放射性及其产物柠檬酸。这证明了我们的假设，即 DCA 是一种抗代谢物，可拮抗乙酸在癌细胞中至关重要的反应。乙酸可用作解毒剂来对抗 DCA 毒性。