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.
Highlights
L-Ascorbic acid (Vitamin C, AA), which is known as an antioxidant, acts as a pro-oxidant in cancer cells and selectively kills cancer cells when administered at a high dose[1]
Analysis of the uptake of L-ascorbic acid by cells using high performance liquid chromatography (HPLC) showed that uptake of L-ascorbic acid was proportional to sodium-dependent vitamin C transporter family 2 (SVCT-2) expression (Fig. 1C)
Other studies revealed that SVCT-2 expression is a determination factor of L-ascorbic acid cancer treatment[30] and that hypoxia-inducible factor–positive cells are susceptible to L-ascorbic acid treatment[16]
Summary
L-Ascorbic acid (Vitamin C, AA), which is known as an antioxidant, acts as a pro-oxidant in cancer cells and selectively kills cancer cells when administered at a high dose[1]. Previous controversial clinical studies[12,13,14,15], including (1) the sufficient dose of L-ascorbic acid for various cancer cells, (2) the reason behind the poor survival rate of patients treated with high-dose L-ascorbic acid, which was even lower than that of the placebo group, in the Mayo Clinic study[14,15]; and (3) whether the anti-cancer activity of L-ascorbic acid changes when the plasma concentration of the delivered L-ascorbic acid decreases and is maintained at a low level for about 4 hours in blood[17] due to spontaneous oxidization over a short period of time[18] We hypothesized that these issues can be explained by the hormetic dose response, which is known as the biphasic dose response in the pharmacological concept and is explained by a U-shaped curve[19], that was observed in several cancer research studies[20,21,22,23,24,25,26]. Since insufficient ROS for cellular apoptosis promotes proliferation of cancer cells through insulin-like growth factor-127 and activation of the Ras gene[28], we propose that insufficient uptake of L-ascorbic results in proliferation of cancer cells
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