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Exp Cell Res. 2014 Feb 15;321(2):219-30. doi: 10.1016/j.yexcr.2013.12.009. Epub 2013 Dec 14.

Dichloroacetate attenuates hypoxia-induced resistance to 5-fluorouracil in gastric cancer through the regulation of glucose metabolism.

Author information

1
Department of Surgery, Ajou University School of Medicine, Suwon 443-749, Republic of Korea; Institute for Gastric Cancer Mechanism, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
2
Department of Surgery, Ajou University School of Medicine, Suwon 443-749, Republic of Korea; Institute for Gastric Cancer Mechanism, Ajou University School of Medicine, Suwon 443-749, Republic of Korea. Electronic address: hhcmc75@naver.com.
3
Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
4
Medical Research Institute, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
5
Department of Pathology, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
6
Institute for Gastric Cancer Mechanism, Ajou University School of Medicine, Suwon 443-749, Republic of Korea; Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
7
Department of Surgery, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.

Abstract

In this study, we 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 profiles 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 20mM 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 relative to the normal gastric 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 20mM 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.

KEYWORDS:

5-Flurouracil; Chemoresistance; Dichloroacetate; Gastric neoplasm; Hypoxia; Pyruvate dehydrogenase kinase

PMID:
24342832
DOI:
10.1016/j.yexcr.2013.12.009
[Indexed for MEDLINE]

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