Cell death induced by N-methyl-N-nitrosourea, a model SN1 methylating agent, in two lung cancer cell lines of human origin

Abstract

New therapeutic approaches are needed for lung cancer, the leading cause of cancer death. Methylating agents constitute a widely used class of anticancer drugs, the effect of which on human non small cell lung cancer (NSCLC) has not been adequately studied. N-methyl-N-nitrosourea (MNU), a model SN1 methylating agent, induced cell death through a distinct mechanism in two human NSCLC cell lines studied, A549(p53wt) and H157(p53null). In A549(p53wt), MNU induced G2/M arrest, accompanied by cdc25A degradation, hnRNP B1 induction, hnRNP C1/C2 downregulation. Non-apoptotic cell death was confirmed by the lack of increase in the sub-G1 DNA content, Poly (ADP-ribose) polymerase cleavage and caspase-3, -7 activation. In H157(p53 null), MNU induced apoptotic cell death, confirmed by cytofluorometry of DNA content and immunodetection of apoptotic markers, accompanied by overexpression of hnRNP B1 and C1/C2. Thus, the mechanism of the cell death induced by SN1 methylating agents is cell type-dependent and must be assessed prior treatment. © 2009 Springer Science+Business Media, LLC