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

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.

• Authors: Yun-Xin Lu, Qi-Nian Wu, Dong-Liang Chen, Le-Zong Chen, Zi-Xian Wang, Chao Ren, Hai-Yu Mo, Ya Chen, Hui Sheng, Ying-Nan Wang, Yun Wang, Jia-Huan Lu, De-Shen Wang, Zhao-Lei Zeng, Feng Wang, Feng-Hua Wang, Yu-Hong Li, Huai-Qiang Ju, Rui-Hua Xu
• Journal: Theranostics (Theranostics) Vol. 8 Issue 5 Pg. 1312-1326 ( 2018) ISSN: 1838-7640 [Electronic] Australia
• PMID: 29507622 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Glucose Transporter Type 1
• Reactive Oxygen Species
• Oxaliplatin
• Irinotecan
• Glutathione
• Ascorbic Acid

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Ascorbic Acid (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Synergism
• Female
• Glucose Transporter Type 1 (metabolism)
• Glutathione (metabolism)
• Humans
• Irinotecan (pharmacology)
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Models, Biological
• Oxaliplatin (pharmacology)
• Oxidation-Reduction
• Oxidative Stress (drug effects)
• Prognosis
• Reactive Oxygen Species (metabolism)
• Stomach Neoplasms (metabolism, pathology)
• Treatment Outcome
• Xenograft Model Antitumor Assays