Tannic acid suppresses vitamin C’s hormetic effects in HCT-15 low-SVCT2-expressing colorectal cancer cells by upregulating SVCT2

Intracellular vitamin C (ascorbic acid, AA) uptake by sodium-dependent vitamin C transporter (SVCT2) is critical for high-dose AA therapy in colorectal cancer. However, hormetic responses to AA treatment are dependent on SVCT2 expression level. In low-SVCT2-expressing colorectal cancer cells, low intracellular AA enhances cancer cell proliferation. Therefore, SVCT2 induction is necessary to increase intracellular AA and thus improve its anti-cancer effects. We report the anticancer effects of combined tannic acid (TA) and AA treatment. In HCT-15 colorectal cancer cells with low SVCT2 expression, TA treatment upregulated SVCT2 expression, which increased the expression of transcription factor and its co-activator, resulting in high intracellular levels of AA (exerting a pro-oxidant effect), thus inducing reactive oxygen species (ROS) generation and increasing the percentage of apoptosis cells. Expression of apoptosis-related markers (Bcl-2, BAX, cleaved caspase-9, and cleaved caspase-3) was regulated after treatment with the combination. Furthermore, in a mouse xenograft model, TA induced SVCT2 expression in the tumor, and combined administration of TA with AA impaired tumor growth. These results suggest that TA suppresses the hormetic effects of AA by upregulating SVCT2 expression, which induces intracellular AA uptake and improves the potential for high-dose AA cancer therapy.