Skip to main content

Advertisement

SpringerLink
Log in

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

  • Educational Series
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chambon P, Weill JD, Mandel P (1963) Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem Biophys Res Commun 11:39–43

    Article  PubMed  CAS  Google Scholar 

  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 6:139

    Article  PubMed  CAS  Google Scholar 

  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 94:7303–7307

    Article  PubMed  Google Scholar 

  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 274:17860–17868

    Article  PubMed  CAS  Google Scholar 

  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 22:2255–2263

    Article  PubMed  CAS  Google Scholar 

  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): 249–268

    Article  PubMed  CAS  Google Scholar 

  7. Yu SW, Wang H, Dawson TM et al (2003) Poly(ADP-ribose) polymerase-1 and apoptosis inducing factor in neurotoxicity. Neurobiol Dis 14:303–317

    Article  PubMed  CAS  Google Scholar 

  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 114:3771–3778

    PubMed  CAS  Google Scholar 

  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 31:4959–4964

    Article  PubMed  CAS  Google Scholar 

  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 65:10145–10148

    Article  PubMed  CAS  Google Scholar 

  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) 3:1103–1108

    Article  CAS  Google Scholar 

  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 66:5744–5756

    Article  PubMed  CAS  Google Scholar 

  13. Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441:437–443

    Article  PubMed  CAS  Google Scholar 

  14. Woon EC, Threadgill MD (2005) Poly(ADP-ribose)polymerase inhibition — where now? Curr Med Chem 12:2373–2392

    Article  PubMed  CAS  Google Scholar 

  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 101:1433–1441

    Article  PubMed  CAS  Google Scholar 

  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 264:4312–4317

    PubMed  CAS  Google Scholar 

  17. Southan GJ, Szabo C (2003) Poly(ADP-ribose) polymerase inhibitors. Curr Med Chem 10:321–340

    PubMed  CAS  Google Scholar 

  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 111:813–818

    Article  PubMed  CAS  Google Scholar 

  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 6:19–25

    PubMed  CAS  Google Scholar 

  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 511:145–178

    Article  PubMed  CAS  Google Scholar 

  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 277:23028–23036

    Article  PubMed  CAS  Google Scholar 

  22. Curtin NJ (2005) PARP inhibitors for cancer therapy. Expert Rev Mol Med 7:1–20

    Article  PubMed  Google Scholar 

  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 96:56–67

    PubMed  CAS  Google Scholar 

  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 58:410–419

    PubMed  CAS  Google Scholar 

  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 5:564–574

    Article  PubMed  CAS  Google Scholar 

  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 63:6008–6015

    PubMed  CAS  Google Scholar 

  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 20:199–203

    Article  PubMed  CAS  Google Scholar 

  28. Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921

    Article  PubMed  CAS  Google Scholar 

  29. Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917

    Article  PubMed  CAS  Google Scholar 

  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 4:703–706

    PubMed  CAS  Google Scholar 

  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 4:934–936

    Article  PubMed  CAS  Google Scholar 

  32. Edwards SL, Brough R, Lord CJ et al (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451:1111–1115

    Article  PubMed  CAS  Google Scholar 

  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 27:1368–1377

    Article  PubMed  CAS  Google Scholar 

  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 48:5100–5103

    Article  PubMed  CAS  Google Scholar 

  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 61:4175–4183

    PubMed  CAS  Google Scholar 

  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 32:456–464

    Article  PubMed  CAS  Google Scholar 

  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 9:5370–5379

    PubMed  CAS  Google Scholar 

  38. Plummer ER (2006) Inhibition of poly(ADP-ribose) polymerase in cancer. Curr Opin Pharmacol 6:364–368

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Instituto de Parasitología y Biomedicina López Neyra, CSIC, Avda. Conocimiento s/n, ES-18100, Granada, Spain

    Andreína Peralta-Leal, María Isabel Rodríguez & Francisco Javier Oliver

Authors
  1. Andreína Peralta-Leal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. María Isabel Rodríguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francisco Javier Oliver
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francisco Javier Oliver.

Additional information

Supported by an unrestricted educational grant from Pfizer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peralta-Leal, A., Rodríguez, M.I. & Oliver, F.J. Poly(ADP-ribose)polymerase-1 (PARP-1) in carcinogenesis: potential role of PARP inhibitors in cancer treatment. Clin Transl Oncol 10, 318–323 (2008). https://doi.org/10.1007/s12094-008-0207-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-008-0207-8

Keywords

Search

Navigation