- Letter to the Editor
- Open Access
- Open Peer Review
© Anwar et al.; licensee BioMed Central. 2015
- Received: 11 July 2014
- Accepted: 26 December 2014
- Published: 17 January 2015
Poly (ADP-ribose) polymerases, abbreviated as PARPs, are a group of familiar proteins that play a central role in DNA repair employing the base excision repair (BER) pathway. There about 17 proteins in this family out of which the primary nuclear PARPs are PARP-1, PARP-2, PARP-3, and tankyrases 1 and 2 (PARP-5a and -5b) .The PARP family members are known to engage in a wide range of cellular activities, for example, DNA repair, transcription, cellular signaling, cell cycle regulation and mitosis amongst others. The chief functional units of PARP-1 are an amino terminal DNA binding domain (DBD), a central auto modification domain (AMD), and a carboxyl-terminal catalytic domain (CD). PARP inhibitors are currently undergoing clinical trials as targeted treatment modalities of breast, uterine, colorectal and ovarian cancer. This review summarizes current insights into the mechanism of action of PARP inhibitors, its recent clinical trials, and potential next steps in the evaluation of this promising class of anti-cancer drugs.
- Poly (ADP-ribose) polymerases
Poly (ADP-ribose) polymerases, abbreviated as PARPs, are a group of familiar proteins that play a central role in DNA repair employing the base excision repair (BER) pathway. These nuclear proteins possess enzymatic and scaffolding properties and govern the repair of single strand breaks in DNA . A true poly(ADP-ribose) polymerase (PARP) can transfer the first ADP-ribose moiety from nicotinamide adenine dinucleotide (NAD+) to an acceptor protein (preferably to glutamate or lysine residues) and can sequentially add multiple ADP-ribose units to the preceding ones to form poly(ADP-ribose) (pADPr) chains. There about 17 proteins in this family out of which the primary nuclear PARPs are PARP-1, PARP-2, PARP-3, and tankyrases 1 and 2 (PARP-5a and -5b). The PARP family members are known to engage in a wide range of cellular activities, for example, DNA repair, transcription, cellular signaling, cell cycle regulation and mitosis amongst others -.
Environmental exposures and cell replication result in DNA damage that is repaired by a variety of mechanisms, including base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), single strand annealing (SSA), homologous recombination (HR), and nonhomologous end joining (NHEJ). Poly (ADP-ribose) polymerases (PARPs) are a family of proteins involved in DNA repair that utilize the BER pathway and share enzymatic and scaffolding properties. PARP1 and PARP2 are the best studied members of this family of enzymes. PARP1 has three domains that are responsible for DNA-binding, automodification, and catalysis. DNA cleavage results in the recruitment and binding of PARP1 to the site of damage, with an increase in its catalytic activity, and the formation of long, branched, poly (ADP-ribose) (PAR) chains. PAR has a net negative charge that promotes recruitment of DNA repair proteins involved in the BER pathway to the site of DNA damage, and facilitates removal of PARP1 from damage sites, allowing access to other repair proteins. Apart from its role in BER, PARP1 has been implicated in the HR and NHEJ pathways, suggesting a broader role for this enzyme family in the overall DNA repair process. PARP1 and PARP2 are the ones extensively studied and well known to be stimulated by DNA damage -. The discovery of their existence was made in 1963, and since then over 40 years of extensive research efforts has brought forth the fruitful results of their potential as therapeutic agents for cancer .
Characterized best amongst the PARP super family members; PARP1 has an integrated structure based on many independently folded domains out of which three are the most important. The chief functional units of PARP-1 are an amino terminal DNA binding domain (DBD), a central auto modification domain (AMD), and a carboxyl-terminal catalytic domain (CD) ,. PARP1 is over expressed in a variety of cancers. Its expression has been linked with prognosis of cancers, most notably breast cancer . PARP1 and its product, PAR, can respond to a variety of endogenous and exogenous stress signals including those generated by oxidative, genotoxic, thermal, oncogenic, metabolic and inflammatory stresses. These responses trigger pathological conditions such as cancer, inflammation related diseases, autoimmune diseases, neurodegenerative diseases and metabolic stresses. PARP inhibitors can therefore be followed upon as a therapeutic solution to these pathologic states .
PARP inhibitors in clinical development imitate the nicotinamide moiety of nicotinamide adenine dinucleotide, and bind to the enzyme’s catalytic domain, inhibiting auto modification and subsequent release of the enzyme from the site of DNA damage. Simultaneously, they also impede access of other repair proteins to the site of DNA damage .
PARP inhibitors are currently undergoing clinical trials as targeted treatment modalities for cancer. Environmental and genetic stressors that disrupt the cell cycle are vital to the etiology and progression of cancer. Henceforth, PARP-1 is an indispensible role player in tumour cell development and PARP-1 targeted therapy can positively predict the outcome in cancer therapy. Clinical trials have been undertaken to assess the safety and efficacy profiles of PARP inhibitors for management of breast, uterine, colorectal and ovarian cancers .
The efficacy of these drugs may be due to the phenomenon of synthetic lethality. This phenomenon targets cells deficient in one DNA repair pathway by inhibiting another. Tumor cells in which the BRCA gene is mutated are unable to repair DSBs by HRR and hence are reliant on other DNA repair pathways, such as BER pathway, which can preclude the development of double stranded breaks DSBs in DNA. Inhibiting PARP activity and subsequent BER pathway in such cells causes the unrepaired single stranded breaks to develop into double stranded breaks and leads to cell death. Such ‘synthetic lethality’ carries implications for the development of anti-cancer drugs . Some tumors possess faulty Homologous Recombination (HR) mechanisms that arise from acquired flaws in the HR pathway rather than germ line BRCA mutations- this property being known as BRCAness. It can occur as a consequence of epigenetic modifications of BRCA 1/2 and/or mutations in various proteins crucial to HR pathways such as RAD51, RAD54, DSS1, RPA1, ATM, CHK2 and PTEN and has been related to several malignancies including triple-negative breast cancer and sporadic serous ovarian cancer -.
Inhibiting PARP activity uncovers potential of PARP inhibitors as promising candidates for cancer therapy, particularly in BRCA1/2 mutated cancers, alone or in combination with cytotoxic drugs ,,. p53-deficient breast cancer cells treated with a PARP Inhibitor happen to lose resistance to an apoptosis promoting, clinically active antitumor agent called doxorubicin . As we established previously, PARP inhibitors were recently developed on the rationale of synthetic lethality, however this concept was well illustrated by Byrant et all and Farmer et all in 2005. They demonstrated that, breast cancer cells containing germ line mutations in BRCA1 and BRCA 2 genes become sensitized to PARP inhibitors in a PARP1 dependant manner and lose sensitivity to PARP inhibition on regaining BRCA2 functionality . A clinical trial of a PARP inhibitor drug, Olaparib, based on the approach of synthetic lethality, has given successful results (minimal side effects with safely administrable doses) in breast cancers containing BRCA1/2 mutations .
The first PARP inhibitor, Nicotinamide, was identified in 1971. Second generation drugs were recognized subsequently. Although agents having selective activity upon PARP-1 and PARP-2 have been identified, most PARP inhibitors are non-selective, affecting PARP-1 as well as PARP-2 .
As of the present day, PARP inhibitors have been explored either as sole agents in BRCA-1/2 depleted cancer or in cancers possessing BRCA-ness, or combined with other DNA damaging moieties such as ionizing radiation in an expansive array of cancers. There are a total of nine drugs in the hierarchy of phases of drug development -.
AZD2281 (Olaparib) is a small molecule oral PARP1/2 and TNKS inhibitor with the commonly observed toxicities of nausea, vomiting, diarrhea and fatigue ,. It is currently undergoing phase I and phase II clinical trials as single agent or in combination therapy with chemotherapy in different cancers like breast, ovarian and colorectal cancers .
AG-014699 (PF-01367338) Rucaparib is an intravenous PARP inhibitor with no significant toxicities when used alone. It was examined in combination with temozolomide in advanced solid tumors . When this combination was used as a first line intervention in patients with metastatic melanoma, bone marrow toxicity was observed . Currently it is being evaluated in Phase II trials as solo agent in BRCA associated breast and ovarian cancers and in Phase I trials in combination with chemotherapy for advanced solid malignancies .
ABT-888 (Veliparib) is an oral PARP-1/2 inhibitor with decent oral bioavailability and apparent CNS penetration . It is currently being explored in Phase I and II Trials in combination with radiation and chemotherapy, respectively, in various cancer types including breast cancer, colorectal cancer, glioblastoma multiforme and melanoma .
MK-4827 (niraparib), an orally available compound, demonstrating strong PARP-1 and PARP-2 inhibitory activity has the side effects of nausea, vomiting, fatigue and thrombocytopenia . It is currently enrolled in Phase I trials as a single agent or in combination regimens with carboplatin in advance solid cell malignancies .
CEP-9722 is an oral PARP-1/2 inhibitor and a pro-drug of CEP-8983. It has the capability of sensitizing tumor cells in glioblastoma, colon cancer, neuroblastoma and rhabdomyosarcoma to TMZ, irinotecan and radiation without augmenting myelosuppression . It is currently under trial as single agent and in combination therapy with Temoolomide in advanced solid malignancies .
E7016 (GPI-21016) (formerly known as GPI-21016) is an orally bioavailable PARP inhibitor that can enhance tumor radio sensitivity and also synergies with temozolmide and radiation to potentiate their effect . It is also enrolled in an ongoing Phase I trial which is exploring its efficacy in combination with temozolomide in advanced solid tumors and gliomas .
Other orally bioavailable potent PARP inhibitor agents include INO-1001, MP-124 and LT-00673 which are also undergoing Phase I clinical development trials .
Main function of radiotherapy is to produce DNA strand breaks, causing severe DNA damage and leading to cell death. Radiotherapy has the potential to kill 100% of any targeted cells, but the dose required to do so would cause unacceptable side effects to healthy tissue. Radiotherapy therefore can only be given up to a certain level of radiation exposure. Combining radiation therapy with PARP inhibitors offers promise, since the inhibitors would lead to formation of double strand breaks from the single-strand breaks generated by the radiotherapy in tumor tissue with BRCA1/BRCA2 mutations. This combination could therefore lead to either more powerful therapy with the same radiation dose or similarly powerful therapy with a lower radiation dose.
It is astonishing to know that the utility of PARP inhibitors as therapeutic candidates is not limited to their efficacy in treating malignancies. Over the decade, they have emerged with a spectrum of actions that incorporates treating other conditions such as cardiovascular diseases, stroke, metabolic disorders, diabetes, and autoimmunity -.
- Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG: PARP inhibition: PARP1 and beyond. Nat Rev Cancer 2010,10(4):293–301. 10.1038/nrc2812View ArticlePubMedPubMed CentralGoogle Scholar
- Amé JC, Spenlehauer C, de Murcia G: The PARP superfamily. Bioessays 2004,26(8):882–93. 10.1002/bies.20085View ArticlePubMedGoogle Scholar
- Hakmé A, Wong H-K, Dantzer F, Schreiber V: The expanding field of poly (ADP-ribosyl) ation reactions. EMBO Rep 2008,9(11):1094–100. 10.1038/embor.2008.191View ArticlePubMedPubMed CentralGoogle Scholar
- Hassa PO, Hottiger MO. The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Front Biosci. 2008;13:3046.View ArticlePubMedGoogle Scholar
- Schreiber V, Dantzer F, Ame JC, de Murcia G: Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 2006,7(7):517–28. 10.1038/nrm1963View ArticlePubMedGoogle Scholar
- Chang P, Jacobson MK, Mitchison TJ: Poly (ADP-ribose) is required for spindle assembly and structure. Nature 2004,432(7017):645–9. 10.1038/nature03061View ArticlePubMedGoogle Scholar
- Huber A, Bai P, Murcia JM, Murcia G: PARP-1, PARP-2 and ATM in the DNA damage response: functional synergy in mouse development. DNA Repair 2004,3(8):1103–8. 10.1016/j.dnarep.2004.06.002View ArticlePubMedGoogle Scholar
- Chambon P, Weill J, Mandel P: Nicotinamide mononucleotide activation of a new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem Biophys Res Commun 1963,11(1):39–43. 10.1016/0006-291X(63)90024-XView ArticlePubMedGoogle Scholar
- Kummar S, Chen A, Parchment RE, Kinders RJ, Ji J, Tomaszewski JE, et al. Advances in using PARP inhibitors to treat cancer. BMC Med. 2012;10(1):25.View ArticlePubMedPubMed CentralGoogle Scholar
- Rojo F, García-Parra J, Zazo S, Tusquets I, Ferrer-Lozano J, Menendez S, Eroles P, Chamizo C, Servitja S, Ramirez-Merino N: Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer. Ann Oncol 2012,23(5):1156–64. 10.1093/annonc/mdr361View ArticlePubMedGoogle Scholar
- Luo X, Kraus WL: On PAR with PARP: cellular stress signaling through poly (ADP-ribose) and PARP-1. Genes Dev 2012,26(5):417–32. 10.1101/gad.183509.111View ArticlePubMedPubMed CentralGoogle Scholar
- Rowe BP, Glazer PM. Emergence of rationally designed therapeutic strategies for breast cancer targeting DNA repair mechanisms. Breast Cancer Res. 2010;12(2):203.Google Scholar
- McCabe N, Turner NC, Lord CJ, Kluzek K, Białkowska A, Swift S, Giavara S, O’Connor MJ, Tutt AN, Zdzienicka MZ: Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly (ADP-ribose) polymerase inhibition. Cancer Res 2006,66(16):8109–15. 10.1158/0008-5472.CAN-06-0140View ArticlePubMedGoogle Scholar
- Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, Waldman T, Lord CJ, Ashworth A: Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med 2009,1(6–7):315–22. 10.1002/emmm.200900041View ArticlePubMedPubMed CentralGoogle Scholar
- Konstantinopoulos PA, Spentzos D, Karlan BY, Taniguchi T, Fountzilas E, Francoeur N, Levine DA, Cannistra SA: Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol 2010,28(22):3555–61. 10.1200/JCO.2009.27.5719View ArticlePubMedPubMed CentralGoogle Scholar
- Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ: Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009,361(2):123–34. 10.1056/NEJMoa0900212View ArticlePubMedGoogle Scholar
- Bolderson E, Richard DJ, Zhou B-BS, Khanna KK: Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair. Clin Cancer Res 2009,15(20):6314–20. 10.1158/1078-0432.CCR-09-0096View ArticlePubMedGoogle Scholar
- Munoz-Gamez J, Martín-Oliva D, Canuelo A, Nunez M, Ruiz dAJ, de Murcia G, Oliver F, Valenzuela M, Aguilar-Quesada R: PARP inhibition sensitizes p53-deficient breast cancer cells to doxorubicin-induced apoptosis. Biochem J 2005, 386: 119–25. 10.1042/BJ20040776View ArticlePubMedPubMed CentralGoogle Scholar
- Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T: Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase. Nature 2005,434(7035):913–7. 10.1038/nature03443View ArticlePubMedGoogle Scholar
- Davar D, Beumer J, Hamieh L, Tawbi H. Role of PARP inhibitors in cancer biology and therapy. Curr Med Chem. 2012;19(23):3907.View ArticlePubMedPubMed CentralGoogle Scholar
- Ferraris DV: Evolution of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors. From concept to clinic. J Med Chem 2010,53(12):4561–84. 10.1021/jm100012mView ArticlePubMedGoogle Scholar
- Kopetz S, Mita M, Mok I, Sankhala K, Moseley J, Sherman B, et al. First in human phase I study of BSI-201, a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in subjects with advanced solid tumors. J Clin Oncol. 2008;26(15S):3577.Google Scholar
- Fong P, Boss D, Carden C, Roelvink M, De Greve J, Gourley C, et al. AZD2281 (KU-0059436), a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: results from a phase I study. J Clin Oncol. 2008;26(15S):Abstract 5510.Google Scholar
- Yuan Y, Liao Y-M, Hsueh C-T, Mirshahidi HR. Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. J Hematol Oncol. 2011;4(1):16.View ArticlePubMedPubMed CentralGoogle Scholar
- Plummer R, Jones C, Middleton M, Wilson R, Evans J, Olsen A, Curtin N, Boddy A, McHugh P, Newell D: Phase I study of the poly (ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 2008,14(23):7917–23. 10.1158/1078-0432.CCR-08-1223View ArticlePubMedPubMed CentralGoogle Scholar
- Plummer R, Lorigan P, Evans J, Steven N, Middleton M, Wilson R, et al. First and final report of a phase II study of the poly (ADP-ribose) polymerase (PARP) inhibitor, AG014699, in combination with temozolomide (TMZ) in patients with metastatic malignant melanoma (MM). J Clin Oncol. 2006;24(18S):8013.Google Scholar
- Sandhu S, Wenham R, Wilding G, McFadden M, Sun L, Toniatti C, et al. First-in-human trial of a poly (ADP-ribose) polymerase (PARP) inhibitor MK-4827 in advanced cancer patients (pts) with antitumor activity in BRCA-deficient and sporadic ovarian cancers. J Clin Oncol (Meeting Abstracts). 2010;2010:3001.Google Scholar
- Miknyoczki S, Chang H, Grobelny J, Pritchard S, Worrell C, McGann N, Ator M, Husten J, Deibold J, Hudkins R: The selective poly (ADP-ribose) polymerase-1 (2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. Mol Cancer Ther 2007,6(8):2290–302. 10.1158/1535-7163.MCT-07-0062View ArticlePubMedGoogle Scholar
- Russo AL, Kwon H-C, Burgan WE, Carter D, Beam K, Weizheng X, Zhang J, Slusher BS, Chakravarti A, Tofilon PJ: In vitro and in vivo radiosensitization of glioblastoma cells by the poly (ADP-ribose) polymerase inhibitor E7016. Clin Cancer Res 2009,15(2):607–12. 10.1158/1078-0432.CCR-08-2079View ArticlePubMedGoogle Scholar
- Masutani M, Nakagama H, Sugimura T: Poly-ADP-ribosylation in health and disease. Cell Mol Life Sci 2005,62(7–8):769–83. 10.1007/s00018-004-4509-xView ArticlePubMedGoogle Scholar
- Mota RA, Sánchez-Bueno F, Saenz L, Hernández-Espinosa D, Jimeno J, Tornel PL, Martínez-Torrano A, Ramírez P, Parrilla P, Yélamos J: Inhibition of poly (ADP-ribose) polymerase attenuates the severity of acute pancreatitis and associated lung injury. Lab Investig 2005,85(10):1250–62. 10.1038/labinvest.3700326View ArticlePubMedGoogle Scholar
- Pacher P, Szabó C: Role of poly (ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovasc Drug Rev 2007,25(3):235–60. 10.1111/j.1527-3466.2007.00018.xView ArticlePubMedPubMed CentralGoogle Scholar
- Ford AL, Lee J-M. Climbing STAIRs towards clinical trials with a novel PARP-1 inhibitor for the treatment of ischemic stroke. Brain Res. 2011;1410:120.View ArticlePubMedPubMed CentralGoogle Scholar
- Underhill C, Toulmonde M, Bonnefoi H: A review of PARP inhibitors: from bench to bedside. Ann Oncol 2011,22(2):268–79. 10.1093/annonc/mdq322View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.