NITRIC OXIDE-INDUCED APOPTOSIS IN HUMAN PANCREATIC-CARCINOMA CELL-LINES IS ASSOCIATED WITH A G(1)-ARREST AND AN INCREASE OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P21(WAF1 CIP1)/

Nitric oxide (NO) is a messenger molecule with various biological acti vities including DNA damage. In the present study, we examined the inf luence of endogenously produced NO on human pancreatic cell lines. In response to cytokine stimulation (tumor necrosis factor alpha, IFN-gam ma, and interleukin 1 beta), human pancreatic carcinoma cell lines exp ressed the inducible NO synthase that synthesizes NO, detectable as ni trate and nitrite in the culture supernatants. Endogenously produced N O induced apoptosis in all of the tested pancreatic carcinoma cell lin es. In cell cycle analysis, endogenous production of NO revealed a G(1 )-arrest in all of the tested cell lines. This G(1)-arrest was blockab le by addition of N-G-monomethyl-L-arginine. These data indicate that NO induces a G(1)-arrest followed by apoptosis in pancreatic carcinoma cell lines.