Clinical and Translational Oncology

, Volume 10, Issue 6, pp 318–323 | Cite as

Poly(ADP-ribose)polymerase-1 (PARP-1) in carcinogenesis: potential role of PARP inhibitors in cancer treatment

  • Andreína Peralta-Leal
  • María Isabel Rodríguez
  • Francisco Javier Oliver
Educational Series

Abstract

Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear, zinc-finger, deoxyribonucleic acid (DNA)-binding protein that detects specifically DNA strand breaks generated by different genotoxic agents. Whereas activation of PARP-1 by mild genotoxic stimuli facilitates DNA repair and cell survival, severe DNA damage triggers different pathways of cell death, including PARP-mediated cell death through the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. Pharmacological inhibition or genetic ablation of PARP-1 results in a clear benefit in cancer treatment by different mechanisms, including selective killing of homologous recombination-deficient tumor cells, downregulation of tumor-related gene expression, and decrease in the apoptotic threshold in the cotreatment with chemo-and radiotherapy. We summarize in this review the findings and concepts for the role of PARP-1 and poly(ADP-ribosylation) in the regulation of carcinogenesis and some of the preclinical and clinical data available for these agents, together with the challenges facing the clinical development of these agents.

Keywords

PARP-1 Carcinogenesis DNA repair Antineoplasic therapy 

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References

  1. 1.
    Chambon P, Weill JD, Mandel P (1963) Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem Biophys Res Commun 11:39–43PubMedCrossRefGoogle Scholar
  2. 2.
    Otto H, Reche PA, Bazan F et al (2005) In silico characterization of the family of PARP-like poly(ADP-ribosyl)transferases (parts). BMC Genomics 6:139PubMedCrossRefGoogle Scholar
  3. 3.
    de Murcia JM, Niedergang C, Trucco C et al (1997) Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci U S A 94:7303–7307PubMedCrossRefGoogle Scholar
  4. 4.
    Ame JC, Rolli V, Schreiber V et al (1999) PARP-2, a novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem 274:17860–17868PubMedCrossRefGoogle Scholar
  5. 5.
    Menissier de Murcia J, Ricoul M, Tartier L et al (2003) Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse. Embo J 22:2255–2263PubMedCrossRefGoogle Scholar
  6. 6.
    D’Amours D, Desnoyers S, D’silva I et al (1999) Poly (ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 342(Pt 2): 249–268PubMedCrossRefGoogle Scholar
  7. 7.
    Yu SW, Wang H, Dawson TM et al (2003) Poly(ADP-ribose) polymerase-1 and apoptosis inducing factor in neurotoxicity. Neurobiol Dis 14:303–317PubMedCrossRefGoogle Scholar
  8. 8.
    D’Amours D, Sallmann FR, Dixit VM et al (2001) Gain-of-function of poly(ADP-ribose) polymerase-1 upon cleavage by apoptotic proteases: implications for apoptosis. J Cell Sci 114:3771–3778PubMedGoogle Scholar
  9. 9.
    Schultz N, Lopez E, Saleh-Gohari N et al (2003) Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res 31:4959–4964PubMedCrossRefGoogle Scholar
  10. 10.
    Hay T, Jenkins H, Sansom OJ et al (2005) Efficient deletion of normal BRCA2-deficient intestinal epithelium by poly(ADP-ribose) polymerase inhibition models potential prophylactic therapy. Cancer Res 65:10145–10148PubMedCrossRefGoogle Scholar
  11. 11.
    Huber A, Bai P, de Murcia JM et al (2004) Parp-1, PARP-2 and ATM in the DNA damage response: Functional synergy in mouse development. DNA Repair (Amst) 3:1103–1108CrossRefGoogle Scholar
  12. 12.
    Martin-Oliva D, Aguilar-Quesada R, O’Valle F et al (2006) Inhibition of poly(ADP-ribose) polymerase modulates tumor-related gene expression, including hypoxia-inducible factor-1 activation, during skin carcinogenesis. Cancer Res 66:5744–5756PubMedCrossRefGoogle Scholar
  13. 13.
    Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441:437–443PubMedCrossRefGoogle Scholar
  14. 14.
    Woon EC, Threadgill MD (2005) Poly(ADP-ribose)polymerase inhibition — where now? Curr Med Chem 12:2373–2392PubMedCrossRefGoogle Scholar
  15. 15.
    Durkacz BW, Irwin J, Shall S (1981) Inhibition of (ADP-ribose)n biosynthesis retards DNA repair but does not inhibit DNA repair synthesis. Biochem Biophys Res Commun 101:1433–1441PubMedCrossRefGoogle Scholar
  16. 16.
    Rankin PW, Jacobson EL, Benjamin RC et al (1989) Quantitative studies of inhibitors of ADP-ribosylation in vitro and in vivo. J Biol Chem 264:4312–4317PubMedGoogle Scholar
  17. 17.
    Southan GJ, Szabo C (2003) Poly(ADP-ribose) polymerase inhibitors. Curr Med Chem 10:321–340PubMedGoogle Scholar
  18. 18.
    Beneke S, Diefenbach J, Burkle A (2004) Poly(ADP-ribosyl)ation inhibitors: Promising drug candidates for a wide variety of pathophysiologic conditions. Int J Cancer 111:813–818PubMedCrossRefGoogle Scholar
  19. 19.
    Lunec J, George AM, Hedges M et al (1984) Post-irradiation sensitization with the ADP-ribosyl-transferase inhibitor 3-acetamidobenzamide. Br J Cancer Suppl 6:19–25PubMedGoogle Scholar
  20. 20.
    Bernstein C, Bernstein H, Payne CM et al (2002) DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: Fail-safe protection against carcinogenesis. Mutat Res 511:145–178PubMedCrossRefGoogle Scholar
  21. 21.
    Schreiber V, Ame JC, Dolle P et al (2002) Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277:23028–23036PubMedCrossRefGoogle Scholar
  22. 22.
    Curtin NJ (2005) PARP inhibitors for cancer therapy. Expert Rev Mol Med 7:1–20PubMedCrossRefGoogle Scholar
  23. 23.
    Calabrese CR, Almassy R, Barton S et al (2004) Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst 96:56–67PubMedGoogle Scholar
  24. 24.
    Chalmers A, Johnston P, Woodcock M et al (2004) Parp-1, PARP-2, and the cellular response to low doses of ionizing radiation. Int J Radiat Oncol Biol Phys 58:410–419PubMedGoogle Scholar
  25. 25.
    Noel G, Godon C, Fernet M et al (2006) Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the s phase of the cell cycle and involves arrest of DNA synthesis. Mol Cancer Ther 5:564–574PubMedCrossRefGoogle Scholar
  26. 26.
    Veuger SJ, Curtin NJ, Richardson CJ et al (2003) Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res 63:6008–6015PubMedGoogle Scholar
  27. 27.
    Boulton S, Kyle S, Durkacz BW (1999) Interactive effects of inhibitors of poly(ADP-ribose) polymerase and DNA-dependent protein kinase on cellular responses to DNA damage. Carcinogenesis 20:199–203PubMedCrossRefGoogle Scholar
  28. 28.
    Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921PubMedCrossRefGoogle Scholar
  29. 29.
    Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917PubMedCrossRefGoogle Scholar
  30. 30.
    Gallmeier E, Kern SE (2005) Absence of specific cell killing of the BRCA2-deficient human cancer cell line CAPAN1 by poly(ADP-ribose) polymerase inhibition. Cancer Biol Ther 4:703–706PubMedGoogle Scholar
  31. 31.
    McCabe N, Lord CJ, Tutt AN et al (2005) BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of poly (ADP-ribose) polymerase: An issue of potency. Cancer Biol Ther 4:934–936PubMedCrossRefGoogle Scholar
  32. 32.
    Edwards SL, Brough R, Lord CJ et al (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451:1111–1115PubMedCrossRefGoogle Scholar
  33. 33.
    Turner NC, Lord CJ, Iorns E et al (2008) A synthetic lethal SIRNA screen identifying genes mediating sensitivity to a PARP inhibitor. Embo J 27:1368–1377PubMedCrossRefGoogle Scholar
  34. 34.
    Jagtap PG, Baloglu E, Southan GJ et al (2005) Discovery of potent poly(ADP-ribose) polymerase-1 inhibitors from the modification of indeno[1,2-c]isoquinolinone. J Med Chem 48:5100–5103PubMedCrossRefGoogle Scholar
  35. 35.
    Perkins E, Sun D, Nguyen A et al (2001) Novel inhibitors of poly(ADP-ribose) polymerase/PARP1 and PARP2 identified using a cell-based screen in yeast. Cancer Res 61:4175–4183PubMedGoogle Scholar
  36. 36.
    Oliver AW, Ame JC, Roe SM et al (2004) Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2. Nucleic Acids Res 32:456–464PubMedCrossRefGoogle Scholar
  37. 37.
    Tentori L, Leonetti C, Scarsella M et al (2003) Systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma. Clin Cancer Res 9:5370–5379PubMedGoogle Scholar
  38. 38.
    Plummer ER (2006) Inhibition of poly(ADP-ribose) polymerase in cancer. Curr Opin Pharmacol 6:364–368PubMedCrossRefGoogle Scholar

Copyright information

© Feseo 2008

Authors and Affiliations

  • Andreína Peralta-Leal
    • 1
  • María Isabel Rodríguez
    • 1
  • Francisco Javier Oliver
    • 1
  1. 1.Instituto de Parasitología y Biomedicina López NeyraCSICGranadaSpain

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