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 proliferati...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1992-08, Vol.89 (16), p.7703-7707
Main Authors: Rice, William G., Hillyer, Christopher D., Harten, Brad, Schaeffer, Catherine A., Dorminy, Mark, Lackey, Dixon A., Kirsten, Eva, Mendeleyev, Jerome, Buki, Kalman G., Hakam, Alaeddin, Kun, Ernest
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastics
Apoptosis
Benzamides - pharmacology
Biological and medical sciences
Bone marrow cells
Brain Neoplasms
Cell Death - drug effects
Cell Death - physiology
Cell Division - drug effects
Cell Line
Cell lines
Cells, Cultured
Cellular biology
Coumarins - pharmacology
Deoxyribonucleic acid
DNA
DNA Replication
Enzymes
Female
General aspects
Hematopoietic stem cells
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - drug effects
Humans
K562 cells
Kidney cells
Kinetics
Leukemia
Ligands
Macaca mulatta
Medical sciences
Multidisciplinary Sciences
Neutrophils - cytology
Neutrophils - drug effects
Nitroso Compounds - pharmacology
Pharmacology. Drug treatments
Poly(ADP-ribose) Polymerase Inhibitors
Science & Technology
Science & Technology - Other Topics
Stem cells
Stem Cells - cytology
Stem Cells - drug effects
Tumor Cells, Cultured
Tumors
Vero cells
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.89.16.7703