Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2

• Published in: NPJ precision oncology Vol. 2; no. 1; p. 1
• Main Authors: Lv, Hongwei, Wang, Changzheng, Fang, Tian, Li, Ting, Lv, Guishuai, Han, Qin, Yang, Wen, Wang, Hongyang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.01.2018; Nature Publishing Group
• Subjects: 631/67/1059; 631/67/71; Apoptosis; Cancer Research; Cell cycle; DNA damage; Gene Therapy; Human Genetics; Internal Medicine; Liver cancer; Medicine; Medicine & Public Health; Oncology; Patients; Precision medicine; Stem cells; Targeted cancer therapy; Vitamin C
• ISSN: 2397-768X; 2397-768X
• DOI: 10.1038/s41698-017-0044-8

Vitamin C (L-ascorbic acid, ascorbate, VC) is a potential chemotherapeutic agent for cancer patients. However, the anti-tumor effects of pharmacologic VC on hepatocellular carcinoma (HCC) and liver cancer stem cells (CSCs) remain to be fully elucidated. Panels of human HCC cell lines as well as HCC patient-derived xenograft (PDX) models were employed to investigate the anti-tumor effects of pharmacologic VC. The use of VC and the risk of HCC recurrence were examined retrospectively in 613 HCC patients who received curative liver resection as their initial treatment. In vitro and in vivo experiments further demonstrated that clinically achievable concentrations of VC induced cell death in liver cancer cells and the response to VC was correlated with sodium-dependent vitamin C transporter 2 (SVCT-2) expressions. Mechanistically, VC uptake via SVCT-2 increased intracellular ROS, and subsequently caused DNA damage and ATP depletion, leading to cell cycle arrest and apoptosis. Most importantly, SVCT-2 was highly expressed in liver CSCs, which promoted their self-renewal and rendered them more sensitive to VC. In HCC cell lines xenograft models, as well as in PDX models, VC dramatically impaired tumor growth and eradicated liver CSCs. Finally, retrospective cohort study showed that intravenous VC use was linked to improved disease-free survival (DFS) in HCC patients (adjusted HR = 0.622, 95% CI 0.487 to 0.795, p  < 0.001). Our data highlight that pharmacologic VC can effectively kill liver cancer cells and preferentially eradicate liver CSCs, which provide further evidence supporting VC as a novel therapeutic strategy for HCC treatment. Liver cancer: vitamin C preferentially kills cancer stem cells and improves patient outcomes Pharmacologic doses of vitamin C preferentially eradicate liver cancer stem cells and are associated with improved outcomes in patients. A team led by Hong-Yang Wang and Wen Yang from the Second Military Medical University in Shanghai, China, showed that clinically achievable concentrations of vitamin C effectively killed liver cancer cells and preferentially eradicated cancer stem cells in culture and in mouse transplant models. Cells with higher expression levels of a vitamin C transporter protein were more susceptible to the treatment, which explains why cancer stem cells, which highly express this transportor and use it for their own self-renewal, were especially sensitive to take in vitamin C, which led to a cascade that resulted in DNA damage, energy depletion, and ultimately cell death. A retrospective analysis of 613 patients with liver cancer showed that those who received intravenous vitamin C lived longer without disease relapse.