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Dichloroacetate, a inhibitor of pyruvate dehydrogenase kinase-1, attenuates hypoxia-induced resistance to 5-fluorouracil in gastric cancer cells
- Author(s)
- XUANYI
- Advisor
- 한상욱
- Department
- 일반대학원 의학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2014-02
- Language
- eng
- Keyword
- Chemoresistance; Dichloroacetate; 5-Fluorouracil; Gastric neoplasm; Hypoxia; Pyruvate dehydrogenase kinase
- Alternative Abstract
- In this study, I investigated whether gastric cancer with hypoxia-induced resistance to 5-fluorouracil (5-FU) could be re-sensitized following treatment with low-dose dichloroacetate (DCA), an inhibitor of the glycolytic pathway. The expression profile of hypoxia-inducible factor-1α (HIF-1α) and pyruvate dehydrogenase kinase-1 (PDK-1) were analyzed in tissues from 10 patients with gastric cancer who had different responses to adjuvant 5-FU treatment. For the in vitro assays, cell viability and apoptosis were evaluated with and without treatment with 20 mM DCA in the AGS and MKN45 cell lines, as well as in PDK1 knockdown cell lines. The expression levels of HIF-1α and PDK-1 were both elevated in the tumor tissues of most patients who showed recurrence after adjuvant 5-FU treatment. Cellular viability tests showed that these cell lines had a lower sensitivity to 5-FU under hypoxic conditions compared to normoxic conditions. Moreover, the addition of 20 mM DCA only increased the sensitivity of these cells to 5-FU under hypoxic conditions, and the resistance to 5-FU under hypoxia was also attenuated in PDK1 knockdown cell lines. In conclusion, DCA treatment was able to re-sensitize gastric cancer cells with hypoxia-induced resistance to 5-FU through the alteration of glucose metabolism and the enhancement of apoptosis.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Medicine > 3. Theses(Master)
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