The mitochondria-targeted nitroxide JP4-039 augments potentially lethal irradiation damage repair.
It was unknown if a mitochondria-targeted nitroxide (JP4-039) could augment potentially lethal damage repair (PLDR) of cells in quiescence. We evaluated 32D cl 3 murine hematopoietic progenitor cells which were irradiated and then either centrifuged to pellets (to simulate PLDR conditions) or left in exponential growth for 0, 24, 48 or 72 h. Pelleted cells demonstrated cell cycle arrest with a greater percentage in the G(1)-phase than did exponentially growing cells. Irradiation survival curves demonstrated a significant radiation damage mitigation effect of JP4-039 over untreated cells in cells pelleted for 24 h. No significant radiation mitigation was detected if drugs were added 48 or 72 h after irradiation. Electron paramagnetic resonance spectroscopy demonstrated a greater concentration of JP4-039 in mitochondria of 24 h-pelleted cells than in exponentially growing cells. These results establish a potential role of mitochondria-targeted nitroxide drugs as mitigators of radiation damage to quiescent cells including stem cells.
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Malolan S
MS
Rajagopalan
Kanika
K
Gupta
Michael W
MW
Epperly
Darcy
D
Franicola
Xichen
X
Zhang
Hong
H
Wang
Hong
H
Zhao
Vladimir A
VA
Tyurin
Joshua G
JG
Pierce
Valerian E
VE
Kagan
Peter
P
Wipf
Anthony J
AJ
Kanai
Joel S
JS
Greenberger
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects*; D051379:Mice; D008809:Mice, Inbred C3H; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects / Q000528:radiation effects; D009589:Nitrogen Oxides / Q000032:analysis / Q000494:pharmacology*; D011833:Radiation Injuries, Experimental / Q000473:pathology* / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*
D000975:Antioxidants; C544775:JP4-039; D009589:Nitrogen Oxides; D011837:Radiation-Protective Agents