Diisopropylamine dichloroacetate enhances radiosensitization in esophageal squamous cell carcinoma by increasing mitochondria-derived reactive oxygen species levels
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Gaochao Dong1,*, Qiang Chen2,3,*, Feng Jiang1,*, Decai Yu4, Qixing Mao1,2, Wenjie Xia1,2, Run Shi1,2, Jie Wang1, Lin Xu2,1
1Department 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
2Department of The Fourth Clinical College, Nanjing Medical University, Nanjing, Jiangsu, China
3Department of Thoracic Surgery, Xuzhou Centre Hospital, Xuzhou, Jiangsu, China
4Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical College, Nanjing, Jiangsu, China
*These authors contributed equally to this work
Lin Xu, email: email@example.com
Keywords: diisopropylamine dichloroacetate, esophageal squamous cell carcinoma, ROS, radiosensitization
Received: April 21, 2016 Accepted: August 24, 2016 Published: September 08, 2016
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.
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