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http://dx.doi.org/10.5352/JLS.2018.28.12.1469

Dichloroacetate Inhibits the Proliferation of a Human Anaplastic Thyroid Cancer Cell Line via a p53-independent Pathway  

KC, Yam Bahadur (Department of Biomedical Science, Daegu Catholic University)
Poudel, Sunil (Department of Pharmaceutical Science and Technology, Daegu Catholic University)
Jeon, Eon Ju (Department of Internal Medicine, Daegu Catholic University School of Medicine)
Shon, Ho Sang (Department of Internal Medicine, Daegu Catholic University School of Medicine)
Byun, Sung June (Animal Biotechnology Division, National Institute of Animal Science (NIAS), RDA)
Jeoung, Nam Ho (Department of Pharmaceutical Science and Technology, Daegu Catholic University)
Publication Information
Journal of Life Science / v.28, no.12, 2018 , pp. 1469-1476 More about this Journal
Abstract
Occurrence of the Warburg effect in solid tumors causes resistance to cancer chemotherapy, and targeting energy metabolisms such as aerobic glycolysis is a potential strategy for alternative treatment. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), shifts glucose metabolism from aerobic glycolysis to oxidative phosphorylation (OxPhos) in many cancers. In this study, we investigated the anticancer effect of DCA on a human anaplastic thyroid cancer (ATC) cell line, 8505C. We found that DCA selectively inhibits cell proliferation of the 8505C line but not of a normal thyroid line. In 8505C, the cell cycle was arrested at the G1/S phase with DCA treatment as a result of decreased antiapoptotic proteins such as $HIF1{\alpha}$, PDK1, and Bcl-2 and increased proapoptotic proteins such as Bax and p21. DCA treatment enhanced the production of reactive oxygen species which consequently induced cell cycle arrest and apoptosis. Interestingly, DCA treatment not only reduced lactate production but also increased the expression of sodium-iodine symporter, indicating that it restores the OxPhos of glucose metabolism and the iodine metabolism of the ATC. Taken together, our findings suggest that PDK inhibitors such as DCA could be useful anticancer drugs for the treatment of ATC and may also be helpful in combination with chemotherapy and radiotherapy.
Keywords
Anaplastic thyroid cancer; apoptosis; cell cycle arrest; dichloroacetate; Warburg effect;
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