Induction of Endonuclease-Mediated Apoptosis in Tumor Cells by C-nitroso-Substituted Ligands of Poly(ADP-ribose) Polymerase

摘要

Novel C-nitroso compounds, 6-Nitroso-1,2-benzopyrone, and 3-nitrosobenzamidewhichinactivate the eukaryotic nuclear protein poly(ADP-ribose) polymerase (NAD+-poly(adenosine diphosphate D-ribose) ADP-D-ribosyl-transferase, ADPRT, E.C. 2.4.2.30) at one zinc-finger site, completely suppressed the proliferation of leukemic and other malignant human cells and subsequently produced cell death. Tumoricidal concentrations of the drugs were relatively harmless to normal bone marrow progenitor cells and to superoxide formation by neutrophil granulocytes. The cellular mechanism elicited by the C-nitroso compounds consists of apoptosis due to DNA degradation by the nuclear calcium/magnesium-dependent endonuclease. This endonuclease is maintained in a latent form by poly-ADP-ribosylation, but inactivation of ADPRT by C-nitroso drugs derepresses the DNA-degrading activity. The ADP-D-ribosyl transferase protein is thus identified as a critical regulatory enzyme component of a DNA-binding multiprotein system that plays a central function in defining DNA structures in the intact cell.