Abstract
Experimental and clinical evidence has indicated that the natural product ascorbic acid (AA) is effective in preventing and treating various types of cancers. However, the effect of AA on liver cancer metastasis has not yet been reported. Cancer stem cells (CSCs) play pivotal roles in cancer metastasis. Here, we demonstrated that AA selectively inhibited the viability of both liver cancer cells and CSCs, reduced the formation of cancer cell colonies and CSC spheres, and inhibited tumor growth in vivo. Additionally, AA prevented liver cancer metastasis in a xenotransplantation model without suppressing stemness gene expression in liver CSCs. Further study indicated that AA increased the concentration of H2O2 and induced apoptosis in liver CSCs. Catalase attenuated the inhibitory effects of AA on liver CSC viability. In conclusion, AA inhibited the viability of liver CSCs and the growth and metastasis of liver cancer cells in vitro and in vivo by increasing the production of H2O2 and inducing apoptosis. Our findings provide evidence that AA exerts its anti-liver cancer efficacy in vitro and in vivo, in a manner that is independent of stemness gene regulation.
Highlights
One of the main causes of cancer-related death is distant metastasis that occurs in cancer patients, and cancer stem cells (CSCs) are an important driving force for cancer metastasis
ascorbic acid (AA) Selectively Inhibited the Viability of Liver Cancer Cells and Liver Cancer stem cells (CSCs) in vitro Two human liver cancer cell lines (Huh7 and Hep3B), the respective CSCs, and a normal human liver cell line L02 were treated with AA at the concentrations of 0, 0.5, or 1 mM, which are achievable clinically by intravenous infusion (Chen et al, 2008) (Hoffer et al, 2008)
The results showed that AA inhibited the viabilities of liver cancer cells and liver CSCs in a concentrationdependent manner (Figures 1A–D)
Summary
One of the main causes of cancer-related death is distant metastasis that occurs in cancer patients, and cancer stem cells (CSCs) are an important driving force for cancer metastasis. CD26+ CSCs caused distant metastasis when injected into the mouse cecal wall, while the presence of CD26+ CSCs in primary tumors can predict distant metastasis in cancer patients (Pang et al, 2010). Lgr5+ or CD44v6+ CSCs are required for the generation of metastatic tumors (Todaro et al, 2014; De Sousa e Melo et al, 2017). In squamous cell carcinoma of the head and neck, it was observed that BMI1+ CSCs regulated the invasive growth and cervical lymph node metastasis in a mouse model (Chen D. et al, 2017). A recent study at the singlecell level in breast cancer has shown that early-stage metastatic cells possess a distinct stem-like gene expression signature (Wylie et al, 2015)
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