Different signalling pathways mediate the opposite effects of endogenous versus exogenous nitric oxide on hydroperoxide toxicity in CHP100 neuroblastoma cells.
The results presented in this study indicate that the toxic response brought about by increasing concentrations of tert-butylhydroperoxide in CHP100 cells was mitigated significantly by exogenously added nitric oxide donors via a cyclic GMP-independent mechanism. In contrast with these results, endogenous nitric oxide generated by the Ca2+-mobilizing agent caffeine was found to increase hydroperoxide toxicity. Under these conditions, nitric oxide was not directly toxic to the cells. Rather, nitric oxide was found to promote the caffeine-mediated release of Ca2+ from ryanodine-sensitive Ca2+ stores via a cyclic GMP-independent mechanism. Release of the cation from ryanodine-sensitive Ca2+ stores was causally linked with the caffeine/nitric oxide-mediated enhancement of tert-butylhydroperoxide toxicity. It is concluded that endogenous and exogenous nitric oxide activate diverging signalling pathways independent of cyclic GMP formation and causing opposite effects on the toxic response evoked by tert-butylhydroperoxide in CHP100 cells.
Guidarelli
A
A
Istituto di Farmacologia e Farmacognosia and Centro di Farmacologia Oncologica Sperimentale, Università di Urbino, Italy.
Clementi
E
E
Sciorati
C
C
Cantoni
O
O
D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D007700:Kinetics; D009447:Neuroblastoma; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured; D020122:tert-Butylhydroperoxide / Q000633:toxicity*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011810:Quinoxalines; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D002110:Caffeine; D026423:S-Nitroso-N-Acetylpenicillamine; D020122:tert-Butylhydroperoxide; D006162:Guanylate Cyclase; D010396:Penicillamine; D006152:Cyclic GMP; D002118:Calcium