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. 1992 Aug 15;89(16):7703–7707. doi: 10.1073/pnas.89.16.7703

Induction of endonuclease-mediated apoptosis in tumor cells by C-nitroso-substituted ligands of poly(ADP-ribose) polymerase.

W G Rice 1, C D Hillyer 1, B Harten 1, C A Schaeffer 1, M Dorminy 1, D A Lackey 3rd 1, E Kirsten 1, J Mendeleyev 1, K G Buki 1, A Hakam 1, et al.
PMCID: PMC49779  PMID: 1502187

Abstract

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Asselin B. L., Ryan D., Frantz C. N., Bernal S. D., Leavitt P., Sallan S. E., Cohen H. J. In vitro and in vivo killing of acute lymphoblastic leukemia cells by L-asparaginase. Cancer Res. 1989 Aug 1;49(15):4363–4368. [PubMed] [Google Scholar]
  2. Berger N. A., Berger S. J., Gerson S. L. DNA repair, ADP-ribosylation and pyridine nucleotide metabolism as targets for cancer chemotherapy. Anticancer Drug Des. 1987 Oct;2(2):203–209. [PubMed] [Google Scholar]
  3. Berger N. A. Poly(ADP-ribose) in the cellular response to DNA damage. Radiat Res. 1985 Jan;101(1):4–15. [PubMed] [Google Scholar]
  4. Birnboim H. C., Jevcak J. J. Fluorometric method for rapid detection of DNA strand breaks in human white blood cells produced by low doses of radiation. Cancer Res. 1981 May;41(5):1889–1892. [PubMed] [Google Scholar]
  5. Buki K. G., Bauer P. I., Mendeleyev J., Hakam A., Kun E. Destabilization of Zn2+ coordination in ADP-ribose transferase (polymerizing) by 6-nitroso-1,2-benzopyrone coincidental with inactivation of the polymerase but not the DNA binding function. FEBS Lett. 1991 Sep 23;290(1-2):181–185. doi: 10.1016/0014-5793(91)81255-7. [DOI] [PubMed] [Google Scholar]
  6. Cole G. A., Bauer G., Kirsten E., Mendeleyev J., Bauer P. I., Buki K. G., Hakam A., Kun E. Inhibition of HIV-1 IIIb replication in AA-2 and MT-2 cells in culture by two ligands of poly (ADP-ribose) polymerase: 6-amino-1,2-benzopyrone and 5-iodo-6-amino-1,2-benzopyrone. Biochem Biophys Res Commun. 1991 Oct 31;180(2):504–514. doi: 10.1016/s0006-291x(05)81093-9. [DOI] [PubMed] [Google Scholar]
  7. Eyer P., Kampffmeyer H., Maister H., Rösch-Oehme E. Biotransformation of nitrosobenzene, phenylhydroxylamine, and aniline in the isolated perfused rat liver. Xenobiotica. 1980 Jul-Aug;10(7-8):499–516. doi: 10.3109/00498258009033785. [DOI] [PubMed] [Google Scholar]
  8. Hillyer C. D., Tiegerman K. O., Berkman E. M. Increase in circulating colony-forming units-granulocyte-macrophage during large-volume leukapheresis: evaluation of a new cell separator. Transfusion. 1991 May;31(4):327–332. doi: 10.1046/j.1537-2995.1991.31491213297.x. [DOI] [PubMed] [Google Scholar]
  9. Juarez-Salinas H., Sims J. L., Jacobson M. K. Poly(ADP-ribose) levels in carcinogen-treated cells. Nature. 1979 Dec 13;282(5740):740–741. doi: 10.1038/282740a0. [DOI] [PubMed] [Google Scholar]
  10. Kaufmann S. H., Brunet G., Talbot B., Lamarr D., Dumas C., Shaper J. H., Poirier G. Association of poly(ADP-ribose) polymerase with the nuclear matrix: the role of intermolecular disulfide bond formation, RNA retention, and cell type. Exp Cell Res. 1991 Feb;192(2):524–535. doi: 10.1016/0014-4827(91)90072-3. [DOI] [PubMed] [Google Scholar]
  11. Kirsten E., Bauer P. I., Kun E. Cellular regulation of ADP-ribosylation of proteins. IV. Conversion of poly(ADP-ribose) polymerase activity to NAD-glycohydrolase during retinoic acid-induced differentiation of HL60 cells. Exp Cell Res. 1991 May;194(1):1–8. doi: 10.1016/0014-4827(91)90122-b. [DOI] [PubMed] [Google Scholar]
  12. Kirsten E., Bauer P. I., Kun E. Suppression of dexamethasone-stimulated DNA synthesis in an oncogene construct containing rat cell line by a DNA site-oriented ligand of poly-ADP-ribose polymerase: 6-amino-1,2-benzopyrone. Exp Cell Res. 1991 Mar;193(1):1–4. doi: 10.1016/0014-4827(91)90530-8. [DOI] [PubMed] [Google Scholar]
  13. Kirsten E., Minaga T., Kun E. Coincidence of subnuclear distribution of poly(ADP-ribose) synthetase and DNA polymerase beta in nuclei of normal and regenerating liver. FEBS Lett. 1982 Mar 8;139(1):117–120. doi: 10.1016/0014-5793(82)80500-0. [DOI] [PubMed] [Google Scholar]
  14. Kun E., Abood L. G. Colorimetric Estimation of Succinic Dehydrogenase by Triphenyltetrazolium Chloride. Science. 1949 Feb 11;109(2824):144–146. doi: 10.1126/science.109.2824.144. [DOI] [PubMed] [Google Scholar]
  15. Kyprianou N., English H. F., Isaacs J. T. Activation of a Ca2+-Mg2+-dependent endonuclease as an early event in castration-induced prostatic cell death. Prostate. 1988;13(2):103–117. doi: 10.1002/pros.2990130203. [DOI] [PubMed] [Google Scholar]
  16. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  17. Nagao M., Nakayasu M., Aonuma S., Shima H., Sugimura T. Loss of amplified genes by poly(ADP-ribose) polymerase inhibitors. Environ Health Perspect. 1991 Jun;93:169–174. doi: 10.1289/ehp.9193169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rice W. G., Weiss S. J. Regulation of proteolysis at the neutrophil-substrate interface by secretory leukoprotease inhibitor. Science. 1990 Jul 13;249(4965):178–181. doi: 10.1126/science.2371565. [DOI] [PubMed] [Google Scholar]
  19. Sastry S. S., Buki K. G., Kun E. Binding of adenosine diphosphoribosyltransferase to the termini and internal regions of linear DNAs. Biochemistry. 1989 Jun 27;28(13):5670–5680. doi: 10.1021/bi00439a050. [DOI] [PubMed] [Google Scholar]
  20. Sastry S. S., Kun E. Molecular interactions between DNA, poly(ADP-ribose) polymerase, and histones. J Biol Chem. 1988 Jan 25;263(3):1505–1512. [PubMed] [Google Scholar]
  21. Tseng A., Jr, Lee W. M., Jakobovits E. B., Kirsten E., Hakam A., McLick J., Buki K., Kun E. Prevention of tumorigenesis of oncogene-transformed rat fibroblasts with DNA site inhibitors of poly(ADP ribose) polymerase. Proc Natl Acad Sci U S A. 1987 Feb;84(4):1107–1111. doi: 10.1073/pnas.84.4.1107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Walker P. R., Smith C., Youdale T., Leblanc J., Whitfield J. F., Sikorska M. Topoisomerase II-reactive chemotherapeutic drugs induce apoptosis in thymocytes. Cancer Res. 1991 Feb 15;51(4):1078–1085. [PubMed] [Google Scholar]
  23. Yoshihara K., Tanigawa Y., Burzio L., Koide S. S. Evidence for adenosine diphosphate ribosylation of Ca2+, Mg2+-dependent endonuclease. Proc Natl Acad Sci U S A. 1975 Jan;72(1):289–293. doi: 10.1073/pnas.72.1.289. [DOI] [PMC free article] [PubMed] [Google Scholar]

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