Mitochondria-targeted (2-hydroxyamino-vinyl)-triphenyl-phosphonium releases NO(.) and protects mouse embryonic cells against irradiation-induced apoptosis.
Generation of reactive oxygen species by damaged respiratory chain followed by the formation of cytochrome c (cyt c)-cardiolipin (CL) complex with peroxidase activity are early events in apoptosis. By quenching the peroxidase activity of cyt c-CL complexes in mitochondria, nitric oxide can exert anti-apoptotic effects. Therefore, mitochondria-targeted pro-drugs capable of gradual nitric oxide radical (NO*) release are promising radioprotectants. Here we demonstrate that (2-hydroxyamino-vinyl)-triphenyl-phosphonium effectively accumulates in mitochondria, releases NO* upon mitochondrial peroxidase reaction, protects mouse embryonic cells from irradiation-induced apoptosis and increases their clonogenic survival after irradiation. We conclude that mitochondria-targeted peroxidase-activatable NO-donors represent a new interesting class of radioprotectors.
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Natalia A
NA
Belikova
Jianfei
J
Jiang
Detcho A
DA
Stoyanovsky
Ashley
A
Glumac
Hülya
H
Bayir
Joel S
JS
Greenberger
Valerian E
VE
Kagan
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology* / Q000528:radiation effects; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D005720:Gamma Rays; D006898:Hydroxylamines / Q000493:pharmacokinetics / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000493:pharmacokinetics / Q000494:pharmacology
C528230:(2-hydroxyaminovinyl)triphenylphosphonium; D006898:Hydroxylamines; D020030:Nitric Oxide Donors; D009943:Organophosphorus Compounds; D011837:Radiation-Protective Agents; D009569:Nitric Oxide