Figure 3.

The anti-cancer effects of Ph-Asc. Pharmacologic ascorbate (Ph-Asc) in the presence of transition metals such as iron (Fe) induces the generation of H₂O₂ and the most powerful known oxidizing agent, hydroxyl radical. In this way, Ph-Asc treatment induces extended oxidative DNA damage that initiates PARP1-dependent repair process which lead to significant NAD⁺ and consequent ATP consumption. mtDNA proved to be more susceptible due to its less efficient repair system. Ph-Asc also induces the PHD2-independent downregulation of HIF-1α. Ph-Asc could inhibit the phosphorylation of PKM2 that halted the nuclear translocation of PKM2, resulting in the impairment of the Warburg effect in cancer cells and xenografts. Finally, Ph-Asc treatment could significantly inhibit the activity of both MAPK/ERK and PI3K/AKT signalling. All the observed cancer cytotoxicity could be reversed by intracellular or extracellular catalase supplementation.