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.

Hepatomas are exquisitely sensitive to pharmacologic ascorbate (P-AscH-)

“…c-Myc protein expression also increased after treatment with 4.0 pmol cell -1 ascorbate but decreased with 10 pmol cell -1 ascorbate (Figure 1N). These findings are consistent with previous studies which showed oncogenic signals such as Ras and c-myc are involved in the process of hepatocarcinogenesis and regulate the expression of metabolic enzymes which induce cancer cell death by apoptosis 35-37.…”

Oxygen Availability during Growth Modulates the Phytochemical Profile and the Chemo-Protective Properties of Spinach Juice

“…In the reported experiment, the best antioxidant effect is recorded when the 5% juice solution is administered to HT29 cells. The observed hormetic behavior resembles the response of cancer cell lines to vitamin C and plant flavonoids, which confirms the evidence reported in literature where an excess of exogenous antioxidants can alter the endogenous antioxidant balance and affects, in turn, the defense response [46,47,48]. Thus, only the 1% and 5% juice concentrations (which showed a marked antioxidant effect) have been chosen for further experiments.…”

Therapeutic Use of Vitamin C in Cancer: Physiological Considerations

“…Therefore, SVCT2 might be implicated in the ascorbate induced cancer cell death phenomena. Similar results were observed by two groups in cholangiocarcinoma cells (Wang et al, 2017), hepatocellular carcinoma (Lv et al, 2018) and colon cancer cells (Cho et al, 2018), where SVCT2 expression determines the susceptibility to pharmacological ascorbate-induced cell death.…”