Abstract
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.
Highlights
Liver cancer is the sixth most frequent cancer and the second leading cause of cancer-related death worldwide.[1]
These pathological properties may flow from cancer stem cells (CSCs), which are capable of self-renewal and differentiation responsible for tumor progression, metastasis, and chemotherapy-resistance.[3,4]
We found that sodium-dependent vitamin C transporter 2 (SVCT-2) expression was dramatically increased in the spheres derived from Hepatocellular carcinoma (HCC) cells compared with the corresponding adherent cells (Fig. 1f, g)
Summary
Liver cancer is the sixth most frequent cancer and the second leading cause of cancer-related death worldwide.[1]. The originally reported studies using intravenous VC produces much higher plasma concentrations than the subsequent trials employing oral VC.[10] More recently, Chen et al have revealed that ascorbate at pharmacologic concentrations (0.3–20 mM) achieved only by intravenously (i.v.) administration selectively kills a variety of cancer cell lines in vitro, but has little cytotoxic effect on normal cells.[11,12,13] high-dose parenteral VC administration represses the growth of numerous cancers in xenografts models including pancreatic cancer, ovarian cancer, prostate cancer, colon cancer, mesothelioma, breast cancer, and neuroblastoma.[13,14,15,16] These observations have reactivated interest in anti-tumor effect of pharmacological VC globally.
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