PMID- 15258257
OWN - NLM
STAT- MEDLINE
DCOM- 20041126
LR  - 20131121
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 66
IP  - 4
DP  - 2004 Oct
TI  - Differential mechanisms of nitric oxide- and peroxynitrite-induced cell death.
PG  - 1043-53
AB  - Nitric oxide (NO) contributes to cellular degeneration in various disorders, 
      particularly in the nervous system. NO targets cell proteins such as soluble 
      guanylyl cyclase, but its detrimental effects are generally attributed to its 
      reaction product with superoxide, peroxynitrite. To understand the mechanisms of 
      NO-induced cell stress, we studied the effects of the NO donors 
      diethylenetriamine and spermine NONOate and the peroxynitrite donor 
      5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride (SIN-1) in SH-SY5Y and 
      NG108-15 neuroblastoma cells. All three compounds induced a dose- and 
      time-dependent decrease in viable cells, which was not blocked by the soluble 
      guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. The two 
      NONOates were approximately 15-fold more potent in SH-SY5Y than in NG108-15 
      cells, whereas the EC50 values of SIN-1 in SH-SY5Y and NG108-15 cells were in the 
      same order. This led us to conclude that the mechanisms of NO and peroxynitrite 
      did not converge. This was supported by our other findings. NONOates induced DNA 
      fragmentation and an increase in cellular caspase-3 activity that preceded the 
      gradual decline in cell viability. In contrast, SIN-1 induced a transient decline 
      in ATP levels and a delayed loss of cell viability with no significant increase 
      in caspase-3 activity or DNA laddering. Moreover, post-treatment with insulin 
      inhibited caspase-3 activation and loss of cell viability in NONOate- but not in 
      SIN-1-exposed cells. These findings suggest that NO is a potent toxin independent 
      of peroxynitrite formation.
FAU - Meij, Johanna T A
AU  - Meij JT
AD  - Department of Cell Biology, University of Cincinnati College of Medicine, 3125 
      Eden Avenue, OH 45267-0521, USA. meijjt@ucmail.uc.edu
FAU - Haselton, Carole L
AU  - Haselton CL
FAU - Hillman, Kristin L
AU  - Hillman KL
FAU - Muralikrishnan, Dhanasekaran
AU  - Muralikrishnan D
FAU - Ebadi, Manuchair
AU  - Ebadi M
FAU - Yu, Lei
AU  - Yu L
LA  - eng
GR  - 1R01-DA09444/DA/NIDA NIH HHS/United States
GR  - 2R01-NS34566-07/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20040716
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Nitric Oxide Donors)
RN  - 14691-52-2 (Peroxynitrous Acid)
RN  - 31C4KY9ESH (Nitric Oxide)
SB  - IM
MH  - Animals
MH  - *Cell Death
MH  - Cell Survival/drug effects
MH  - Humans
MH  - Hybridomas
MH  - Mice
MH  - Nitric Oxide/*pharmacology
MH  - Nitric Oxide Donors/antagonists & inhibitors/*pharmacology
MH  - Peroxynitrous Acid/*pharmacology
MH  - Rats
MH  - Time Factors
MH  - Tumor Cells, Cultured
EDAT- 2004/07/20 05:00
MHDA- 2004/12/16 09:00
CRDT- 2004/07/20 05:00
PHST- 2004/07/20 05:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2004/07/20 05:00 [entrez]
AID - mol.104.001354 [pii]
AID - 10.1124/mol.104.001354 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2004 Oct;66(4):1043-53. doi: 10.1124/mol.104.001354. Epub 2004 Jul 
      16.