Enhanced Anticancer Effect of Adding Magnesium to Vitamin C Therapy: Inhibition of Hormetic Response by SVCT-2 Activation.

l-Ascorbic acid (vitamin C, AA) is known as an antioxidant, but at high concentrations, AA can kill cancer cells through a prooxidant property. Sodium-dependent vitamin C transporter family-2 (SVCT-2) determines the cellular uptake of AA, and the activity of SVCT-2 is directly related to the anticancer activity of AA. Cancer cells that showed high SVCT-2 expression levels were more sensitive to AA treatment than cancer cells with low SVCT-2 expression levels. Cells with low SVCT-2 expression showed a hormetic response to a low dose of AA. Magnesium ions, which are known to activate SVCT-2, could increase the Vmax value of SVCT-2, so we investigated whether providing magnesium supplements to cancer cells with low SVCT-2 expression that had shown a hormetic response to AA would elevate the Vmax value of SVCT-2, allowing more AA to accumulate. To evaluate the effects of magnesium on cancer cells, MgSO4 and MgCl2 were screened as magnesium supplements; both forms showed synergistic anticancer effects with AA. Taken together, the results of this study suggest that magnesium supplementation enhanced the anticancer effect of AA by inhibiting the hormetic response at a low dose. This study has also demonstrated that AA treatment with magnesium supplementation provided more effective anticancer therapy than AA treatment alone.

Yeast (1 → 3)-(1 → 6)-ß-d-glucan alleviates immunosuppression in gemcitabine-treated mice.

Gemcitabine (2'-deoxy-2',2'-difluorocytidine, dFdC) is one of the most effective chemotherapy drugs commonly used for treatment of various tumors. Despite its significant anticancer effects, some adverse effects create obstacles to treatment. The main toxicity of gemcitabine is myelosuppression, which not only reduces patient quality of life, but also hinders further anticancer treatment. In this respect, immunotherapy can address these drawbacks because of its ability to enhance the patient's immune system. To improve immune system function, yeast-derived ß-glucans, which are well-known biologic response modifiers, were administered to gemcitabine-treated mice. The in vivo experiment revealed that orally administered yeast (1 → 3)-(1 → 6)-ß-d-glucan effectively alleviated myelosuppression associated with gemcitabine-induced pancytopenia. Moreover, analysis of myelopoiesis-related cytokine expression through real-time PCR demonstrated that ß-glucan treatment significantly upregulated hematopoietic responses in gemcitabine-treated mice. Furthermore, orally administered ß-glucan significantly induced the expression of IFN-γ and IL-2 in splenocytes of gemcitabine-treated mice. It also restored the cytotoxicity of splenocytes against YAC-1 in gemcitabine-treated mice and displayed a positive effect on gemcitabine-damaged bone marrow tissue. In conclusion, yeast ß-glucans have the potential to be used as adjuvants for alleviating chemotherapy-induced immunosuppression in patients.

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

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.