Ascorbic acid predominantly kills cancer stem cell-like cells in the hepatocellular carcinoma cell line Li-7 and is more effective at low cell density and in small spheroids.

The development of therapies that target cancer stem cells (CSCs) is an important challenge in cancer research. The antioxidant system is enhanced in CSCs, which may lead to resistance to existing therapies. Ascorbic acid (AA) has the potential to act as both an antioxidant and a pro-oxidant agent, but its effects on CSCs are a subject of current research. Here, we investigated the effect of AA focusing specifically on CSCs with the hepatocellular carcinoma cell line Li-7. The Li-7 cell line is heterogenous consisting of CD166 ^- and CD166 ⁺ cells; CD166 ^- cells include CSC-like cells (CD13 ⁺ CD166 ^- cells) and CD13 ^- CD166 ^- cells that can revert to CD13 ⁺ CD166 ^- cells. The addition of AA to the culture medium caused cell death in both cell populations in CD166 ^- cells in a concentration dependent manner. In contrast, AA administration had a limited effect on CD166 ⁺ non-CSC cells. The level of reactive oxygen species after AA treatment was elevated only in CD166 ^- cells. The effect of AA only occurred at low cell densities in 2D and 3D cultures. In a mouse tumor model injected with Li-7 cells, intraperitoneal administration of AA failed to prevent tumor formation but appeared to delay tumor growth. Our findings shed light on why AA administration has not become a mainstream treatment for cancer treatment; however, they also show the possibility that AA can be used in therapies to suppress CSCs.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Yukio Nakamura reports financial support was provided by Government of Japan Ministry of Education Culture Sports Science and Technology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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