Author: Schoenfeld, J.D.; Sibenaller, Z.A.; Mapuskar, K.A.; Wagner, B.A.; Cramer-Morales, K.L.; Furqan, M.; Sandhu, S.; Carlisle, T.L.; Smith, M.C.; Abu Hejleh, T.; Berg, D.J.; Zhang, J.; Keech, J.; Parekh, K.R.; Bhatia, S.; Monga, V.; Bodeker, K.L.; Ahmann, L.; Vollstedt, S.; Brown, H.; Shanahan Kauffman, E.P.; Schall, M.E.; Hohl, R.J.; Clamon, G.H.; Greenlee, J.D.; Howard, M.A.; Schultz, M.K.; Smith, B.J.; Riley, D.P.; Domann, F.E.; Cullen, J.J.; Buettner, G.R.; Buatti, J.M.; Spitz, D.R.; Allen, B.G.
Description: 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.
Subject headings: Animals; Antineoplastic Combined Chemotherapy Protocols/therapeutic use; Ascorbic Acid/administration & dosage/adverse effects/pharmacology; Brain Neoplasms/drug therapy; Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism/mortality/radiotherapy; Cell Line, Tumor; Chemoradiotherapy/methods; Female; Glioblastoma/drug therapy/metabolism; Humans; Hydrogen Peroxide/pharmacology; Iron/metabolism; Lung Neoplasms/drug therapy/metabolism/mortality/radiotherapy; Male; Mice, Nude; Oxygen/metabolism; Radiation-Sensitizing Agents/pharmacology; Xenograft Model Antitumor Assays; ferritin; glioblastoma multiforme; hydrogen peroxide; labile iron metabolism; non-small cell lung cancer; oxidative stress; pharmacological ascorbate; superoxide; superoxide dismutase; transferrin receptor
Publication year: 2017
Journal or book title: Cancer Cell
Volume: 31
Issue: 4
Pages: 487-500.e8
Find the full text :Â https://europepmc.org/article/pmc/pmc5497844
Find more like this one (cited by):Â https://scholar.google.com/scholar?cites=9043453505635929568&as_sdt=1000005&sciodt=0,16&hl=en
Type: Journal Article
Serial number: 2122