Induction of apoptosis and G2/M arrest by N-methyl-N'-nitro-N-nitrosoguanidine in human prostate carcinoma cells.

We have investigated the effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a well known DNA alkylating agent, on the growth and cell cycle progression in human prostate carcinoma PC-3 and DU145 cells, which are lacking both p53 alleles and having mutated p53, respectively. It was found that MNNG could inhibit the cell growth in a dose-dependent manner, which was associated with dendrite-like morphological change and induction of apoptotic cell death. Flow cytometry showed that MNNG could cause an arrest at the G2/M phase of the cell cycle, which is closely correlated to inhibition of cyclin-dependent kinase (Cdk) 2 and Cdc2 kinase activities. Furthermore, this compound induced Cdk inhibitor p21WAF1/CIP1 expression at both the transcription and protein levels in a p53-independent manner. MNNG also activated the reporter construct of a p21 promoter. Present results indicate that the up-regulation of p21 by MNNG is likely responsible for the inhibition of Cdks kinase activity rather than the down-regulation of cyclins and Cdks expression.