Induction of apoptosis and inhibition of cyclooxygenase-2 expression by N-methyl-N'-nitro-N-nitrosoguanidine in human leukemia cells

Abstract

Previous studies have demonstrated that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a well-known DNA alkylating agent, induces G2/M arrest and apoptotic cell death in several human cancer cell lines. In the present study, we investigated the effects of MNNG on the growth of a U937 human leukemia cell model. The effects of this compound were also tested on cyclooxygenase (COX) activity. Treatment of U937 cells with MNNG resulted in the inhibition of viability and the induction of apoptosis in a concentration-dependent manner, which was associated with a dose-dependent upregulation in pro-apoptotic Bax protein, downregulation of anti-apoptotic Bcl-2 and Bcl-xL proteins, and proteolytic activation of caspase-3 protease. Furthermore, MNNG decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with inactivation of the reporter construct of a COX-2 promoter and decrease in prostaglandin E2 synthesis. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of MNNG.