High dose vitamin C in metastatic lung cancer and glioblastoma multiforme:
- High-dose ascorbate sensitizes NSCLC and GBM cells to radio-chemotherapy
- O2⋅− and H2O2 increase labile iron causing cancer cell-selective ascorbate toxicity
- Therapeutic levels of ascorbate are achievable and well tolerated in GBM and NSCLC
- Cancer cell oxidative metabolism can be targeted with ascorbate for cancer therapy
Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅− and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.