Induction of endonuclease-mediated apoptosis in tumor cells by C-nitroso-substituted ligands of poly(ADP-ribose) polymerase.
6-Nitroso-1,2-benzopyrone and 3-nitrosobenzamide, two C-nitroso compounds that inactivate the eukaryotic nuclear protein poly(ADP-ribose) polymerase [NAD+:poly(adenosine diphosphate D-ribose) ADP-D-ribosyltransferase, ADPRT, EC 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-ribosyl)ation, but inactivation of ADPRT by C-nitroso drugs derepresses the DNA-degrading activity. ADPRT 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.
Rice
W G
WG
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322.
Hillyer
C D
CD
Harten
B
B
Schaeffer
C A
CA
Dorminy
M
M
Lackey
D A
DA
Kirsten
E
E
Mendeleyev
J
J
Buki
K G
KG
Hakam
A
A
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001932:Brain Neoplasms; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D003374:Coumarins / Q000494:pharmacology*; D004261:DNA Replication; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D007938:Leukemia; D008024:Ligands; D008253:Macaca mulatta; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects; D009603:Nitroso Compounds / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D014407:Tumor Cells, Cultured
D001549:Benzamides; D003374:Coumarins; D008024:Ligands; D009603:Nitroso Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C071196:6-nitroso-1,2-benzopyrone; C076039:3-nitrosobenzamide