Evidence for the role of nitric oxide in antiapoptotic and genotoxic effect of nicotine on human gingival fibroblasts.
Resistance to apoptosis is essential for cancer survival and plays a critical role in carcinogenesis. Growing evidence suggests that nicotine can act as a tumor promoter, impairing apoptotic process in certain types of human cancer cell lines. Our previous study revealed in human gingival fibroblasts (HGFs) a concomitant antiapoptotic and genotoxic effect of nicotine, manifested by the attenuation of staurosporine (STP)-induced apoptosis and the increase of micronucleus frequency. The present report provides evidence that nitric oxide (NO) is critically involved in these actions. In vitro treatment with sodium nitroprusside as NO donor showed that NO produced similar effects as those observed with nicotine: it caused DNA damage and partially prevented apoptosis induced by staurosporine. Exposure of HGFs to nicotine, at concentrations similar to those found in the blood of habitual smokers, leads to the production of NO associated with the induction of inducible nitric oxide synthase (iNOS) expression. Experiments using an inhibitor of iNOS, N-monomethyl-L-arginine (NMA), together with nicotine confirmed the involvement of NO in the drug action, abrogating completely cell death and a good part of the genotoxicity. Finally, we show by different approaches that the inhibition of cell death by nicotine through NO release is related to modulation of caspase-1 activation.
Argentin
Gabriella
G
Department of Odontological Sciences, University of Rome Tor Vergata.
Cicchetti
Rosadele
R
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology*; D005881:Gingiva / Q000166:cytology*; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D009538:Nicotine / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology
D009153:Mutagens; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D009569:Nitric Oxide; D009538:Nicotine; D052247:Nitric Oxide Synthase Type II; D020170:Caspase 1; D019311:Staurosporine