Protection of normal brain cells from γ-irradiation-induced apoptosis by a mitochondria-targeted triphenyl-phosphonium-nitroxide: a possible utility in glioblastoma therapy.
Glioblastoma multiforme is the most frequent and aggressive primary brain tumor. A strong rationale to identify innovative approaches to treat these tumors is required since treatment failures result in local recurrences and median survivals range from 9 to 12 months. Glioma cells are reported to have less mitochondrial content compared to adjacent normal brain cells. Based on this difference, we suggest a new strategy, utilizing protection of normal brain cells by mitochondria-targeted electron scavengers and antioxidants-nitroxides-thus allowing for the escalation of the radiation doses. In this paper, we report that a conjugate of nitroxide with a hydrophobic cation, triphenyl-phosphonium (TPEY-Tempo), significantly protected brain endothelial cells from γ-irradiation-induced apoptosis while radiosensitizing brain tumor cells. Thus, TPEY-Tempo may be a promising adjunct in the treatment of glioblastoma with the potential to not only prolong survival but also to maintain quality of life and reduce treatment toxicity.
Huang
Zhentai
Z
Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Jiang
Jianfei
J
Belikova
Natalia A
NA
Stoyanovsky
Detcho A
DA
Kagan
Valerian E
VE
Mintz
Arlan H
AH
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D001921:Brain / Q000166:cytology*; D001932:Brain Neoplasms / Q000473:pathology / Q000648:ultrastructure; D053148:Caspase 3 / Q000378:metabolism; D002461:Cell Line, Transformed; D003497:Cyclic N-Oxides / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D003576:Electron Transport Complex IV / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000528:radiation effects / Q000648:ultrastructure; D005720:Gamma Rays / Q000009:adverse effects; D005910:Glioma / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000737:chemistry*; D009930:Organic Chemicals / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*
D003497:Cyclic N-Oxides; C507919:MitoTracker Red 580; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D009930:Organic Chemicals; D016566:Organoselenium Compounds; C092819:triphenylselenonium chloride; D045304:Cytochromes c; D003576:Electron Transport Complex IV; D053148:Caspase 3; C003959:TEMPO