Hormetic dose response to L-ascorbic acid as an anti-cancer drug in colorectal cancer cell lines according to SVCT-2 expression

Abstract L -Ascorbic acid (vitamin C, AA) exhibits anti-cancer effects with high-dose treatment through the generation of reactive oxygen species (ROS) and selective damage to cancer cells. The anti-cancer effects of L -ascorbic acid are determined by sodium-dependent vitamin C transporter 2 (SVCT-2), a transporter of L -ascorbic acid. In this study, we demonstrate that L -ascorbic acid treatment showed efficient anti-cancer activity in cell lines with high expression levels of SVCT-2 for a gradient concentration of L -ascorbic acid from 10 μM −2 mM. However, in low SVCT-2 expressing cell lines, high-dose L -ascorbic acid (>1 mM) showed anti-cancer effects but low-dose (<10 μM) treatment induced cell proliferation. Such conflicting results that depend on the concentration are called a hormetic dose response. A hormetic dose response to low-dose L -ascorbic acid was also observed in high SVCT-2 expressing cell lines in the presence of a SVCT family inhibitor. Insufficient uptake of L -ascorbic acid in low SVCT-2 expressing cancer cell lines cannot generate sufficient ROS to kill cancer cells, resulting in the hormetic response. Molecular analysis confirmed the increased expression of cancer proliferation markers in the hormetic dose response. These results suggest that L -ascorbic exhibits a biphasic effect in cancer cells depending on SVCT-2 expression.