title: Dichloroacetate restores drug sensitivity in paclitaxel-resistant cells by inducing citric acid accumulation.
abstract: 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.
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China. zhouxiang1103@126.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China. crh19870405@163.com.
authors.forename: Ruohua
authors.initials: R
authors.lastname: Chen
authors.affiliation: School of biomedical engineering, Shanghai Jiao Tong University, Shanghai, China. tomsyu@163.com.
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China. alcefay@163.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China. kcguy@163.com.
authors.forename: Jiajin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China. zxp0856@sina.com.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China. shaoli-song@163.com.
authors.forename: Shaoli
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China. ljjsh@133sh.com.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China. huang2802@163.com.|Department of Cancer Metabolism, Institute of Health Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School Medicine, Shanghai, China. huang2802@163.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D019343:Citric Acid / Q000378:metabolism*; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004351:Drug Resistance / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D019343:Citric Acid; D003999:Dichloroacetic Acid; D017239:Paclitaxel