Fig. 4.

Differential response of ascorbate at a pharmacological dose on GBM cell and normal cell. The difference in H₂O₂ metabolism and iron metabolism is the signature of ascorbate selectivity toward cancer cells. Oxidation of ascorbate in the extracellular space produces H₂O₂ that enters the cell. In normal cells, ascorbate enters using SVCT2 and exhibits a high ability to metabolize H₂O₂, therefore iron metabolism is well maintained resulting in low cellular levels of labile iron (Fe²⁺). In GBM cells, dehydroascorbate enters using GLUT1; however, SVCT2 functionality is changed resulting in a change in the amount of ascorbate within cancer cells (dotted line) which hampers H₂O₂ metabolism. Subsequently, there is a build-up of H₂O₂ and disturbance in iron metabolism to enhance the levels of labile iron (Fe²⁺) within cancer cells. The intercellular conversion of ascorbate to dehydroascorbate aids in this process. The enhanced accumulation of cellular Fe²⁺ triggers free radical production, as well as decreased redox equivalent resulting in making GBM cells susceptible to vitamin C. Red arrows indicate downstream events and red lines indicate inhibition. ↑ indicates activation and ↓ indicates suppression. GLUT1, glucose transporter 1; H₂O₂, hydrogen peroxide; IRP1, iron regulatory protein 1; SVCT2, sodium-dependent vitamin C transporter 2