Diisopropylamine dichloroacetate enhances radiosensitization in esophageal squamous cell carcinoma by increasing mitochondria-derived reactive oxygen species levels.
Radiotherapy is generally applied in the treatment of esophageal squamous cell carcinoma (ESCC). However, the radioresistance of ESCC still remains an obstacle for the curative effect of this treatment. We hypothesized that diisopropylamine dichloroacetate (DADA), an inhibitor of pyruvate dehydrogenase kinase (PDK), might enhance radiosensitizationin resistant ESCC. The clonogenic survival assay revealed that DADA sensitized ESCC cells to radiotherapy in vitro; furthermore, the combination of DADA and radiotherapy increased the expression of γ-H2AX, which is a hallmark of DNA double-strand breaks. Arrest at G2/M phase as well as the induction of apoptosis of ESCC cells were also observed in the cells treated with the combination of DADA and radiotherapy. Notably, xenograft tumor growth was significantly suppressed in vivo by combined radiotherapy and DADA administration. It has been proven that glycolysis is highly correlated with radioresistance, which could be reversed by the shift from glycolysis to mitochondrial oxidation. In our present study, we found that DADA could modulate oxidative phosphorylation as well as increase the intracellular levels of reactive oxygen species (ROS). Collectively, we concluded that DADA-induced intracellular ROS accumulation was identified as the key factor of radiotherapy sensitization of ESCC.
Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
Gaochao
G
Dong
Department of The Fourth Clinical College, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Thoracic Surgery, Xuzhou Centre Hospital, Xuzhou, Jiangsu, China.
Qiang
Q
Chen
Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
Feng
F
Jiang
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical College, Nanjing, Jiangsu, China.
Decai
D
Yu
Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.|Department of The Fourth Clinical College, Nanjing Medical University, Nanjing, Jiangsu, China.
Qixing
Q
Mao
Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.|Department of The Fourth Clinical College, Nanjing Medical University, Nanjing, Jiangsu, China.
Wenjie
W
Xia
Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.|Department of The Fourth Clinical College, Nanjing Medical University, Nanjing, Jiangsu, China.
Run
R
Shi
Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
Jie
J
Wang
Department of The Fourth Clinical College, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
Lin
L
Xu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000532:radiotherapy; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000644:Quaternary Ammonium Compounds; D017382:Reactive Oxygen Species; C001002:diisopropylamine dichloroacetate
ROS; diisopropylamine dichloroacetate; esophageal squamous cell carcinoma; radiosensitization