Theranostics 2018; 8(5):1312-1326. doi:10.7150/thno.21745

Research Paper

Pharmacological Ascorbate Suppresses Growth of Gastric Cancer Cells with GLUT1 Overexpression and Enhances the Efficacy of Oxaliplatin Through Redox Modulation

Yun-Xin Lu1,2,*, Qi-Nian Wu1,2,*, Dong-liang Chen1,2,*, Le-Zong Chen1,2,*, Zi-Xian Wang1,2, Chao Ren1,2, Hai-yu Mo1, Ya Chen1, Hui Sheng1, Ying-Nan Wang1,2, Yun Wang1,2, Jia-Huan Lu1, De-shen Wang1,2, Zhao-lei Zeng1, Feng Wang1,2, Feng-Hua Wang1,2, Yu-Hong Li1,2, Huai-Qiang Ju1✉, Rui-Hua Xu1,2✉

1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China;
2. Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China;
*These authors contributed equally to this work.

Abstract

Rationale: The antitumor activity of high-dose ascorbate has been re-evaluated recently, but the mechanism underlying cell-specific sensitivity to ascorbate has not yet been clarified.

Methods: The effects of high-dose ascorbate on gastric cancer were assessed using cancer cell lines with high and low expression of GLUT1 via flow cytometry and colony formation assays in vitro and patient-derived xenografts in vivo.

Results: In this study, we demonstrated that gastric cancer cells with high GLUT1 expression were more sensitive to ascorbate treatment than cells with low GLUT1 expression. GLUT1 knockdown significantly reversed the therapeutic effects of pharmacological ascorbate, while enforced expression of GLUT1 enhanced the sensitivity to ascorbate treatment. The efficacy of pharmacological ascorbate administration in mice bearing cell line-based and patient-derived xenografts was influenced by GLUT1 protein levels. Mechanistically, ascorbate depleted intracellular glutathione, generated oxidative stress and induced DNA damage. The combination of pharmacological ascorbate with genotoxic agents, including oxaliplatin and irinotecan, synergistically inhibited gastric tumor growth in mouse models.

Conclusions: The current study showed that GLUT1 expression was inversely correlated with sensitivity of gastric cancer cells to pharmacological ascorbate and suggested that GLUT1 expression in gastric cancer may serve as a marker for sensitivity to pharmacological ascorbate.

Keywords: pharmacological ascorbate, gastric cancer, chemotherapy, reactive oxygen species, GLUT1

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How to cite this article:
Lu YX, Wu QN, Chen Dl, Chen LZ, Wang ZX, Ren C, Mo Hy, Chen Y, Sheng H, Wang YN, Wang Y, Lu JH, Wang Ds, Zeng Zl, Wang F, Wang FH, Li YH, Ju HQ, Xu RH. Pharmacological Ascorbate Suppresses Growth of Gastric Cancer Cells with GLUT1 Overexpression and Enhances the Efficacy of Oxaliplatin Through Redox Modulation. Theranostics 2018; 8(5):1312-1326. doi:10.7150/thno.21745. Available from http://www.thno.org/v08p1312.htm