The Mechanism Of Lethal Effect Of High-dose Vitamin C On Renal Cancer Cells

It has been studied for decades about Vitamin C's role in cancer therapy. Clinical research indicated that intravenous ascorbic acid in high concentrations could have a positive effect on cancer treatment. In vitro experiments showed that cancer cells are more easily killed than normal cells. However, the mechanism of cytotoxicity to cancer cells remains unsolved. Here we used CCRCC cells as cancer cell model to study the mechanism of cytotoxicity of Vitamin C to renal cancer cells. We demonstrated that vitamin C could induce cell death depending on HIF activity. HIF activated renal cancer cells could accumulate more intracellular vitamin C through GLUT1 which is usually overexpressed in cancer cells. Those intracellular vitamin C reacted with ferrous and produced more reactive oxygen species (ROS). ROS triggered DNA damage and induced DNA repair pathway which caused NAD+ and ATP consumption suddenly. HIF activated renal cancer cells use aerobic glycosis (Warburg effect) for producing ATP which is less effective and makes them more sensitive to NAD+ and ATP depletion. Thereafter they entered into necrosis because of the poor ability of recovery from ATP depletion. Our results here provided molecular pathway that vitamin C kill renal cancer cells in detail and also the concept that compounds targeting multiple defects of cancer cells might be more effective.