Dichloroacetate restores drug sensitivity in paclitaxel-resistant cells by inducing citric acid accumulation

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• 作者：Xiang Zhou (1)
  Ruohua Chen (1)
  Zhenhai Yu (2)
  Rui Li (1)
  Jiajin Li (1)
  Xiaoping Zhao (1)
  Shaoli Song (1)
  Jianjun Liu (1)
  Gang Huang (1) (3)
  
  1. Department of Nuclear Medicine ; Ren Ji Hospital ; School of Medicine ; Shanghai Jiao Tong University ; 1630 Dongfang Road ; Shanghai ; 200127 ; China
  2. School of biomedical engineering ; Shanghai Jiao Tong University ; Shanghai ; China
  3. Department of Cancer Metabolism ; Institute of Health Sciences ; Chinese Academy of Sciences and Shanghai Jiao Tong University School Medicine ; Shanghai ; China
  
• 关键词：Dichloroacetate ; Paclitaxel ; Mitochondrial respiratory defect ; Pyruvate dehydrogenase kinase ; Warburg effect
• 刊名：Molecular Cancer
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：14
• 期：1
• 全文大小：2,977 KB
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• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

Background The Warburg effect describes the increased reliance of tumor cells on glycolysis for ATP generation. Mitochondrial respiratory defect is thought to be an important factor leading to the Warburg effect in some types of tumor cells. Consequently, there is growing interest in developing anti-cancer drugs that target mitochondria. One example is dichloroacetate (DCA) that stimulates mitochondria through inhibition of pyruvate dehydrogenase kinase. Methods We investigated the anti-cancer activity of DCA using biochemical and isotopic tracing methods. Results We observed that paclitaxel-resistant cells contained decreased levels of citric acid and sustained mitochondrial respiratory defect. DCA specifically acted on cells with mitochondrial respiratory defect to reverse paclitaxel resistance. DCA could not effectively activate oxidative respiration in drug-resistant cells, but induced higher levels of citrate accumulation, which led to inhibition of glycolysis and inactivation of P-glycoprotein. Conclusions The abilityof DCA to target cells with mitochondrial respiratory defect and restore paclitaxel sensitivity by inducing citrate accumulation supports further preclinical development.