Abstract
The process of poly(ADP-ribosyl)ation and the major enzyme that catalyses this reaction, poly(ADP-ribose) polymerase 1 (PARP1), were discovered more than 50 years ago. Since then, advances in our understanding of the roles of PARP1 in cellular processes such as DNA repair, gene transcription and cell death have allowed the investigation of therapeutic PARP inhibition for a variety of diseases — particularly cancers in which defects in DNA repair pathways make tumour cells highly sensitive to the inhibition of PARP activity. Efforts to identify and evaluate potent PARP inhibitors have so far led to the regulatory approval of four PARP inhibitors for the treatment of several types of cancer, and PARP inhibitors have also shown therapeutic potential in treating non-oncological diseases. This Review provides a timeline of PARP biology and medicinal chemistry, summarizes the pathophysiological processes in which PARP plays a role and highlights key opportunities and challenges in the field, such as counteracting PARP inhibitor resistance during cancer therapy and repurposing PARP inhibitors for the treatment of non-oncological diseases.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
£14.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
£139.00 per year
only £11.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gibson, B. A. & Kraus, W. L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol. 13, 411–424 (2012).
Kraus, W. L. PARPs and ADP-ribosylation: 50 years … and counting. Mol. Cell 58, 902–910 (2015).
Cohen, M. S. & Chang, P. Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat. Chem. Biol. 14, 236–243 (2018).
Schuhwerk, H., Atteya, R., Siniuk, K. & Wang, Z. Q. PARPing for balance in the homeostasis of poly(ADP-ribosyl)ation. Semin. Cell Dev. Biol. 63, 81–91 (2017).
Palazzo, L. & Ahel, I. PARPs in genome stability and signal transduction: implications for cancer therapy. Biochem. Soc. Trans. 46, 1681–1695 (2018).
Chambon, P., Weill, J. D., Doly, J., Strosser, M. T. & Mandel, P. On the formation of a novel adenylic compound by enzymatic extracts of liver nuclei. Biochem. Biophys. Res. Commun. 25, 638–643 (1966). This study is the first to describe the formation of PAR.
Nishizuka, Y., Ueda, K., Nakazawa, K. & Hayaishi, O. Studies on the polymer of adenosine diphosphate ribose. I. Enzymic formation from nicotinamide adenine dinuclotide in mammalian nuclei. J. Biol. Chem. 242, 3164–3171 (1967). This study is the first to identify the enzyme PARP1.
Ueda, K., Reeder, R. H., Honjo, T., Nishizuka, Y. & Hayaishi, O. Poly adenosine diphosphate ribose synthesis associated with chromatin. Biochem. Biophys. Res. Commun. 31, 379–385 (1968).
Otake, H., Miwa, M., Fujimura, S. & Sugimura, T. Binding of ADP-ribose polymer with histone. J. Biochem. 65, 145–146 (1969).
Yamada, M., Miwa, M. & Sugimura, T. Studies on poly (adenosine diphosphate-ribose): X. properties of a partially purified poly (adenosine diphosphate-ribose) polymerase. Arch. Biochem. Biophys. 146, 579–586 (1971).
Juarez-Salinas, H., Sims, J. L. & Jacobson, M. K. Poly(ADP-ribose) levels in carcinogen-treated cells. Nature 282, 740–741 (1979). This study documents an increase in PAR formation following DNA damage.
Benjamin, R. C. & Gill, D. M. ADP-ribosylation in mammalian cell ghosts. Dependence of poly(ADP-ribose) synthesis on strand breakage in DNA. J. Biol. Chem. 255, 10493–10501 (1980).
Purnell, M. R. & Whish, W. J. Novel inhibitors of poly(ADP-ribose) synthetase. Biochem. J. 185, 775–777 (1980). This study describes the synthesis of the first PARP inhibitor, 3-AB.
Poirier, G. G., de Murcia, G., Jongstra-Bilen, J., Niedergang, C. & Mandel, P. Poly(ADP-ribosyl)ation of polynucleosomes causes relaxation of chromatin structure. Proc. Natl Acad. Sci. USA 79, 3423–3427 (1982).
Durkacz, B. W., Omidiji, O., Gray, D. A. & Shall, S. (ADP-ribose) participates in DNA excision repair. Nature 283, 593–596 (1980). This study is the first demonstration of the inhibition of DNA repair and increased cytotoxicity of a DNA-methylating agent by a PARP inhibitor.
Sims, J. L., Berger, S. J. & Berger, N. A. Poly(ADP-ribose) polymerase inhibitors preserve nicotinamide adenine dinucleotide and adenosine 5′-triphosphate pools in DNA damaged cells: mechanism of stimulation of unscheduled DNA synthesis. Biochemistry 22, 5188–5194 (1983). This study marks the formulation of the ‘Berger hypothesis’, describing how the activation of PARP can lead to depletion of cellular NAD + and ATP levels.
Schraufstatter, I. U., Hinshaw, D. B., Hyslop, P. A., Spragg, R. G. & Cochrane, C. G. Oxidant injury of cells. DNA strand-breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotinamide adenine dinucleotide. J. Clin. Invest. 77, 1312–1320 (1986).
Suto, M. J., Turner, W. R., Arundel-Suto, C. M., Werbel, L. M. & Sebolt-Leopold, J. S. Dihydroisoquinolinones: the design and synthesis of a new series of potent inhibitors of poly(ADP- ribose) polymerase. Anticancer Drug Des. 6, 107–117 (1991).
Arundel-Suto, C. M., Scavone, S. V., Turner, W. R., Suto, M. J. & Sebolt-Leopold, J. S. Effect of PD 128763, a new potent inhibitor of poly(ADP-ribose) polymerase, on X-ray-induced cellular recovery processes in Chinese hamster V79 cells. Rad. Res. 126, 367–371 (1991).
Banasik, M., Komura, H., Shimoyama, M. & Ueda, K. Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase. J. Biol. Chem. 267, 1569–1575 (1992). This study identifies several commercially available compounds that inhibit PARP. These molecules served as templates for further PARP inhibitor design and development efforts.
Satoh, M. S. & Lindahl, T. Role of poly(ADP-ribose) formation in DNA repair. Nature 356, 356–358 (1992). This is the first demonstration of PARP ‘trapping’.
Zhang, J., Dawson, V. L., Dawson, T. M. & Snyder, S. H. Nitric oxide activation of poly (ADP-ribose) synthetase in neurotoxicity. Science 263, 687–689 (1994).
Heller, B. et al. Inactivation of the poly(ADP-ribose) polymerase gene affects oxygen radical and nitric oxide toxicity in islet cells. J. Biol. Chem. 270, 11176–11180 (1995).
Wang, Z. Q. et al. Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease. Genes Dev. 9, 509–520 (1995). This study describes the generation of the Parp1-knockout mouse.
Szabo, C., Zingarelli, B., O’Connor, M. & Salzman, A. L. DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proc. Natl Acad. Sci. USA 93, 1753–1758 (1996). This study describes how PARP activation occurs in response to nitrosative stress and also describes the protective effect of PARP inhibition against cell death.
Ruf, A., Mennissier de Murcia, J., de Murcia, G. & Schulz, G. E. Structure of the catalytic fragment of poly(AD-ribose) polymerase from chicken. Proc. Natl Acad. Sci. USA 93, 7481–7485 (1996).
Szabo, C. et al. Inhibition of poly (ADP-ribose) synthetase attenuates neutrophil recruitment and exerts anti-inflammatory effects. J. Exp. Med. 186, 1041–1049 (1997). This study demonstrates that PARP inhibition can suppress inflammation.
Wang, Z. Q. et al. PARP is important for genomic stability but dispensable in apoptosis. Genes Dev. 11, 2347–2358 (1997).
de Murcia, J. M. et al. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc. Natl Acad. Sci. USA 94, 7303–7307 (1997).
Meisterernst, M., Stelzer, G. & Roeder, R. G. Poly(ADP-ribose) polymerase enhances activator-dependent transcription in vitro. Proc. Natl Acad. Sci. USA 94, 2261–2265 (1997). This study is the first to link PARP to gene transcription events.
Rawling, J. M. & Alvarez-Gonzalez, R. TFIIF, a basal eukaryotic transcription factor, is a substrate for poly(ADP-ribosyl)ation. Biochem. J. 324, 249–253 (1997).
Eliasson, M. J. et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat. Med. 3, 1089–1095 (1997).
Zingarelli, B., Cuzzocrea, S., Zsengeller, Z., Salzman, A. L. & Szabo, C. Protection against myocardial ischemia and reperfusion injury by 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase. Cardiovasc. Res. 36, 205–215 (1997).
Virag, L., Salzman, A. L. & Szabo, C. Poly(ADP-ribose) synthetase activation mediates mitochondrial injury during oxidant-induced cell death. J. Immunol. 161, 3753–3759 (1998). This study shows PARP overactivation promotes a regulated form of cell necrosis in oxidatively stressed cells.
Amé, J. C. et al. PARP-2, a novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J. Biol. Chem. 274, 17860–17868 (1999). This is the first study to identify PARP2, which then stimulated the search for other PARPs and led to the identification of the PARP superfamily.
Hassa, P. O. & Hottiger, M. O. A role of poly (ADP-ribose) polymerase in NF-κB transcriptional activation. Biol. Chem. 380, 953–959 (1999).
Oliver, F. J. et al. Resistance to endotoxic shock as a consequence of defective NF-κB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J. 18, 4446–4454 (1999).
Oei, S. L. & Ziegler, M. ATP for the DNA ligation step in base excision repair is generated from poly(ADP-ribose). J. Biol. Chem. 275, 23234–23239 (2000).
Soriano, F. G. et al. Diabetic endothelial dysfunction: the role of poly (ADP-ribose) polymerase activation. Nat. Med. 7, 108–113 (2001). This study is the first to link PARP activation to diabetic complications.
Simbulan-Rosenthal, C. M. et al. Misregulation of gene expression in primary fibroblasts lacking poly(ADP-ribose) polymerase. Proc. Natl Acad. Sci. USA 97, 11274–11279 (2000).
Jagtap, P. et al. Novel phenanthridinone inhibitors of poly(adenosine 5′-diphosphate-ribose) synthetase: potent cytoprotective and antishock agents. Crit. Care Med. 30, 1071–1082 (2002).
Liaudet, L. et al. Activation of poly(ADP-ribose) polymerase is a central mechanism of lipopolysaccharide-induced acute pulmonary inflammation. Am. J. Resp. Crit. Care Med. 165, 372–377 (2002).
Yu, S. W. et al. Mediation of poly(ADP-ribose) polymerase-1- dependent cell death by apoptosis-inducing factor. Science 297, 259–263 (2002).
Veres, B. et al. The novel phenanthridinone inhibitor of poly(ADP-ribose) synthetase (PJ34) protects mice against LPS induced septic shock by decreasing inflammatory response and enhancing the cytoprotective Akt/protein kinase B pathway. Biochem. Pharmacol. 65, 1373–1382 (2003).
Menissier de Murcia, J. et al. Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse. EMBO J. 22, 2255–2263 (2003).
Schreiber, V., Dantzer, F., Ame, J. C. & de Murcia, G. Poly(ADP-ribose): novel functions for an old molecule. Nat. Rev. Mol. Cell Biol. 7, 517–528 (2006).
Jagtap, P. G. et al. Discovery of potent poly(ADP-ribose) polymerase-1 inhibitors from the modification of indeno[1,2-c]isoquinolinone. J. Med. Chem. 48, 5100–5103 (2005).
Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005). The studies by Farmer et al. and Bryant et al. (2005) together are the first to identify the synthetic lethality of PARP inhibitors in BRCA-mutant cells and tumours.
Thomas, H. D. et al. Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial. Mol. Cancer Ther. 6, 945–956 (2007).
Menear, K. A. et al. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J. Med. Chem. 51, 6581–6591 (2008).
Andrabi, S. A. et al. Poly(ADP-ribose) (PAR) polymer is a death signal. Proc. Natl Acad. Sci. USA 103, 18308–18313 (2006). This study is the first to recognize PAR as an independent mediator of cell death.
Bai, P. et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 13, 461–468 (2011).
Langelier, M. F., Planck, J. L., Roy, S. & Pascal, J. M. Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1. Science 336, 728–732 (2012).
Kang, H. C. et al. Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage. Proc. Natl Acad. Sci. USA 108, 14103–14108 (2011).
DaRosa, P. A. et al. Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal. Nature 517, 223–226 (2015).
Andrabi, S. A. et al. Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis. Proc. Natl Acad. Sci. USA 111, 10209–10214 (2014).
Wright, R. H. et al. ADP-ribose-derived nuclear ATP synthesis by NUDIX5 is required for chromatin remodeling. Science 352, 1221–1225 (2016).
Kam, T. I. et al. Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease. Science 362, eaat8407 (2018). This study describes PAR-related protein modification as a contributor to neurodegeneration.
Zimmermann, M. et al. CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. Nature 559, 285–289 (2018).
Müller, K. H. et al. Poly(ADP-ribose) links the DNA damage response and biomineralization. Cell Rep. 27, 3124–3138 (2019).
Caron, M. C. et al. Poly(ADP-ribose) polymerase-1 antagonizes DNA resection at double-strand breaks. Nat. Commun. 10, 2954 (2019).
Ruiz, P. D. et al. MacroH2A1 regulation of poly(ADP-ribose) synthesis and stability prevents necrosis and promotes DNA repair. Mol. Cell Biol. 40, e00230–19 (2019).
Masutani, M. et al. Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes. Proc. Natl Acad. Sci. USA 96, 2301–2304 (1999).
Pascal, J. M. & Ellenberger, T. The rise and fall of poly(ADP-ribose): an enzymatic perspective. DNA Repair 32, 10–16 (2015).
Langelier, M. F., Eisemann, T., Riccio, A. A. & Pascal, J. M. PARP family enzymes: regulation and catalysis of the poly(ADP-ribose) posttranslational modification. Curr. Opin. Struct. Biol. 53, 187–198 (2018).
Kraus, W. L. & Hottiger, M. O. PARP-1 and gene regulation: progress and puzzles. Mol. Asp. Med. 34, 1109–1123 (2013).
Ryu, K. W., Kim, D. S. & Kraus, W. L. New facets in the regulation of gene expression by ADP-ribosylation and poly(ADP-ribose) polymerases. Chem. Rev. 115, 2453–2481 (2015).
Wang, Y., Luo, W. & Wang, Y. PARP-1 and its associated nucleases in DNA damage response. DNA Repair 81, 102651 (2019).
Eisemann, T. & Pascal, J. M. Poly(ADP-ribose) polymerase enzymes and the maintenance of genome integrity. Cell. Mol. Life Sci. 21, 1–5 (2020).
Donà, F. et al. Poly(ADP-ribosylation) and neoplastic transformation: effect of PARP inhibitors. Curr. Pharm. Biotechnol. 14, 524–536 (2013).
Rodríguez, M. I. et al. Deciphering the insights of poly(ADP-ribosylation) in tumor progression. Med. Res. Rev. 35, 678–697 (2015).
Bai, P. & Cantó, C. The role of PARP-1 and PARP-2 enzymes in metabolic regulation and disease. Cell Metab. 16, 290–295 (2012).
Vida, A., Márton, J., Mikó, E. & Bai, P. Metabolic roles of poly(ADP-ribose) polymerases. Semin. Cell Dev. Biol. 63, 135–143 (2017).
Gupte, R., Liu, Z. & Kraus, W. L. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes. Genes Dev. 31, 101–126 (2017).
Kunze, F. A. & Hottiger, M. O. Regulating immunity via ADP-ribosylation: therapeutic implications and beyond. Trends Immunol. 40, 159–173 (2019).
Virág, L., Robaszkiewicz, A., Rodriguez-Vargas, J. M. & Oliver, F. J. Poly(ADP-ribose) signaling in cell death. Mol. Asp. Med. 34, 1153–1167 (2013).
Bürkle, A. & Virág, L. Poly(ADP-ribose): PARadigms and PARadoxes. Mol. Asp. Med. 34, 1046–1065 (2013).
Jubin, T. et al. Poly ADP-ribose polymerase-1: beyond transcription and towards differentiation. Semin. Cell Dev. Biol. 63, 167–179 (2017).
Bürkle, A., Grube, K. & Küpper, J. H. Poly(ADP-ribosyl)ation: its role in inducible DNA amplification, and its correlation with the longevity of mammalian species. Exp. Clin. Immunogenet. 9, 230–240 (1992).
Vida, A., Abdul-Rahman, O., Mikó, E., Brunyánszki, A. & Bai, P. Poly(ADP-ribose) polymerases in aging — friend or foe? Curr. Protein Pept. Sci. 17, 705–712 (2016).
Szabó, C. Nicotinamide: a jack of all trades (but master of none?). Int. Care Med. 29, 863–866 (2003).
Burkart, V., Blaeser, K. & Kolb, H. Potent beta-cell protection in vitro by an isoquinolinone-derived PARP inhibitor. Horm. Metab. Res. 31, 641–644 (1999).
Calabrese, C. R. et al. Identification of potent nontoxic poly(ADP-ribose) polymerase-1 inhibitors: chemopotentiation and pharmacological studies. Clin. Cancer Res. 9, 2711–2718 (2003).
Bowman, K. J., White, A., Golding, B. T., Griffin, R. & Curtin, N. J. Potentiation of anticancer agent cytotoxicity by the potent poly(ADP-ribose) polymerase inhibitors, NU1025 and NU1064. Br. J. Cancer 78, 1269–1277 (1998).
Bowman, K. J., Newell, D. R., Calvert, A. H. & Curtin, N. J. Differential effects of the poly(ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity. Br. J. Cancer 84, 106–112 (2001). This study is the first to describe inhibition of DNA repair and enhancement of the cytotoxicity of topoisomerase 1 poisons by PARP inhibition.
McDonald, M. C. et al. Effects of 5-aminoisoquinolinone, a water-soluble, potent inhibitor of the activity of poly (ADP-ribose) polymerase on the organ injury and dysfunction caused by haemorrhagic shock. Br. J. Pharmacol. 130, 843–850 (2000).
Zhang, J. et al. GPI 6150 prevents H2O2 cytotoxicity by inhibiting poly(ADP-ribose) polymerase. Biochem. Biophys. Res. Commun. 278, 590–598 (2000).
Nicolescu, A. C., Holt, A., Kandasamy, A. D., Pacher, P. & Schulz, R. Inhibition of matrix metalloproteinase-2 by PARP inhibitors. Biochem. Biophys. Res. Commun. 387, 646–650 (2009).
Jones, P. et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J. Med. Chem. 52, 7170–7185 (2009).
Shen, Y. et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin. Cancer Res. 19, 5003–5015 (2013).
Donawho, C. K. et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin. Cancer Res. 13, 2728–2737 (2007).
McGonigle, S. et al. E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling. Oncotarget 6, 41307–41323 (2015).
Miknyoczki, S. et al. 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. 6, 2290–2302 (2007).
Tang, Z. et al. BGB-290: A highly potent and specific PARP1/2 inhibitor potentiates anti-tumor activity of chemotherapeutics in patient biopsy derived SCLC models. Cancer Res. 75, S1653 (2015).
Wang, L. et al. Pharmacologic characterization of fluzoparib, a novel poly(ADP-ribose) polymerase inhibitor undergoing clinical trials. Cancer Sci. 110, 1064–1075 (2019).
Kim, Y. et al. Neuroprotective effects of a novel poly (ADP-ribose) polymerase-1 inhibitor, JPI-289, in hypoxic rat cortical neurons. Clin. Exp. Pharmacol. Physiol. 44, 671–679 (2017).
Cao, J. et al. Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors. J. Clin. Oncol. 37, 3059 (2019).
Ferraris, D. V. Evolution of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. From concept to clinic. J. Med. Chem. 53, 4561–4584 (2010).
Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).
Jain, P. G. & Patel, B. D. Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents - a recent update. Eur. J. Med. Chem. 165, 198–215 (2019).
Miller, E. G. Stimulation of nuclear poly (adenosine diphosphate-ribose) polymerase activity from HeLa cells by endonucleases. Biochim. Biophys. Acta 395, 191–200 (1975).
Davies, M. I., Halldorsson, H., Nduka, N., Shall, S. & Skidmore, C. J. The involvement of poly(adenosine diphosphate-ribose) in deoxyribonucleic acid repair. Biochem. Soc. Trans. 6, 1056–1057 (1978).
Skidmore, C. J. et al. The involvement of poly(ADP-ribose) polymerase in the degradation of NAD caused by gamma-radiation and N-methyl-N-nitrosourea. Eur. J. Biochem. 101, 135–142 (1979).
Ben-Hur, E., Chen, C.-C. & Elkind, M. M. Inhibitors of poly(adenosine diphosphoribose)synthetase, examination of metabolic perturbations and enhancement of radiation response in Chinese hamster cells. Cancer Res. 45, 2123–2127 (1985). This is the first demonstration of radiosensitization by PARP inhibition.
Parsons, J. L. & Dianov, G. L. Co-ordination of base excision repair and genome stability. DNA Repair 12, 326–333 (2013).
Krokan, H. E. & Bjørås, M. Base excision repair. Cold Spring Harb. Perspect. Biol. 5, a012583 (2013).
Caldecott, K. W. Protein ADP-ribosylation and the cellular response to DNA strand breaks. DNA Repair 19, 108–113 (2014).
Martin-Hernandez, K., Rodriguez-Vargas, J. M., Schreiber, V. & Dantzer, F. Expanding functions of ADP-ribosylation in the maintenance of genome integrity. Semin. Cell Dev. Biol. 63, 92–101 (2017).
Li, M. & Yu, X. The role of poly(ADP-ribosyl)ation in DNA damage response and cancer therapy. Oncogene 34, 3349–3356 (2015).
Dulaney, C., Marcrom, S., Stanley, J. & Yang, E. S. Poly(ADP-ribose) polymerase activity and inhibition in cancer. Semin. Cell Dev. Biol. 63, 144–153 (2017).
Pascal, J. M. The comings and goings of PARP-1 in response to DNA damage. DNA Repair 71, 177–182 (2018).
Noël, G. et al. Poly(ADP-ribose) polymerase (PARP-1) is not involved in DNA double-strand break recovery. BMC Cell Biol. 4, 7 (2003).
Ali, M. et al. The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but doesn’t enhance the efficacy of doxorubicin despite improving tumour perfusion and radiation response. Mol. Cancer Ther. 10, 2320–2329 (2011).
Evers, B. et al. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin. Cancer Res. 14, 3916–3925 (2008).
Haince, J. F. et al. PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. J. Biol. Chem. 283, 1197–1208 (2008).
Hochegger, H. et al. Parp-1 protects homologous recombination from interference by Ku and Ligase IV in vertebrate cells. EMBO J. 25, 1305–1314 (2006).
Schultz, N., Lopez, E., Saleh-Gohari, N. & Helleday, T. Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res. 31, 4959–4964 (2003).
Hanzlikova, H. et al. The importance of poly(ADP-ribose) polymerase as a sensor of unligated Okazaki fragments during DNA replication. Mol. Cell 71, 319–331.e3 (2018).
Kedar, P. S., Stefanick, D. F., Horton, J. K. & Wilson, S. H. Increased PARP-1 association with DNA in alkylation damaged, PARP-inhibited mouse fibroblasts. Mol. Cancer Res. 10, 360–368 (2012).
Pommier, Y., O’Connor, M. J. & de Bono, J. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci. Transl. Med. 8, 362ps17 (2016).
Murai, J. et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol. Cancer Ther. 13, 433–443 (2014).
Zandarashvili, L. et al. Structural basis for allosteric PARP-1 retention on DNA breaks. Science. 368, eaax6367 (2020).
Min, A. & Im, S. A. PARP inhibitors as therapeutics: beyond modulation of PARylation. Cancers 12, 394 (2020).
Petermann, E., Ziegler, M. & Oei, S. L. ATP-dependent selection between single nucleotide and long patch base excision repair. DNA Repair 2, 1101–1114 (2003).
Lazebnik, Y. A., Kaufmann, S. H., Desnoyers, S., Poirier, G. G. & Earnshaw, W. C. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371, 346–347 (1994). This is the first demonstration of PARP cleavage and its link to apoptosis.
Nicholson, D. W. et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376, 37–43 (1995).
Curtin, N. J. PARP inhibitors for cancer therapy. Expert. Rev. Mol. Med. 7, 1–20 (2005).
Calabrese, C. R. et al. Preclinical evaluation of a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor, AG14361, with significant anticancer chemo- and radio-sensitization activity. J. Nat. Cancer Inst. 96, 56–67 (2004).
Plummer, R. et al. Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin. Cancer Res. 14, 7917–7923 (2008). This article describes the first clinical trial of a PARP inhibitor, in which rucaparib was evaluated in combination with temozolomide.
Lesueur, P. et al. Poly-(ADP-ribose)-polymerase inhibitors as radiosensitizers: a systematic review of pre-clinical and clinical human studies. Oncotarget 8, 69105–69124 (2017).
Powell, C., Mikropoulos, C. & Kaye, S. B. Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers. Cancer Treat. Rev. 36, 566–575 (2010).
Lu, Y., Liu, Y., Pang, Y., Pacak, K. & Yang, C. Double-barreled gun: combination of PARP inhibitor with conventional chemotherapy. Pharmacol. Ther. 188, 168–175 (2018).
Sachdev, E., Tabatabai, R., Roy, V., Rimel, B. J. & Mita, M. M. PARP inhibition in cancer: An update on clinical development. Target. Oncol. 14, 657–679 (2019).
Lindahl, T., Satoh, M. S., Poirier, G. G. & Klungland, A. Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem. Sci. 20, 405–411 (1995).
Saleh-Gohari, N. et al. Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks. Mol. Cell. Biol. 25, 7158–7169 (2005).
Venkitaraman, A. R. Functions of BRCA1 and BRCA2 in the biological response to DNA damage. J. Cell Sci. 114, 3591–3598 (2001).
Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009). This article describes the first clinical trial of a PARP inhibitor as a single agent (olaparib).
De Lorenzo, S. B., Patel, A. G., Hurley, R. M. & Kaufmann, S. H. The elephant and the blind men: Making sense of PARP inhibitors in homologous recombination deficient tumor cells. Front. Oncol. 3, 228 (2013).
Gelmon, K. A. et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 12, 852–861 (2011).
Mukhopadhyay, A. et al. Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to PARP inhibitors. Clin. Cancer Res. 16, 2344–2351 (2010). This is the first demonstration that more than 50% of ovarian cancers are HRR defective.
Konstantinopoulos, P. A. et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J. Clin. Oncol. 28, 3555–3561 (2010).
Jenner, Z. B., Sood, A. K. & Coleman, R. L. Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncol. 12, 1439–1456 (2016).
Gulhan, D. C., Lee, J. J., Melloni, G. E. M., Cortés-Ciriano, I. & Park, P. J. Detecting the mutational signature of homologous recombination deficiency in clinical samples. Nat. Genet. 51, 912–919 (2019).
Ledermann, J., Harter, P., Gourley, C. et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 15, 852–861 (2019). This article describes the clinical trial leading to first approval of olaparib.
Drew, Y. et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br. J. Cancer 114, 723–730 (2016).
Kristeleit, R. et al. A phase I-II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors. Clin. Cancer Res. 23, 4095–4106 (2017).
Swisher, E. M. et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 18, 75–87 (2017).
Oza, A. M. et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2. Gynecol. Oncol. 147, 267–275 (2017).
Coleman, R. L. et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390, 1949–1961 (2017). The studies by Coleman et al., Drew et al. (2016), Kristeleit et al. (2017), Swischer et al. (2017) and Oza et al. (2017) together describe the clinical trials that contributed to the first approval of rucaparib.
Mirza, M. R. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med. 375, 2154–2164 (2016). This study describes the clinical trial leading to the first approval of niraparib.
Moore, K. N. et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 20, 636–648 (2019).
Litton, J. K. et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N. Engl. J. Med. 379, 753–763 (2018). This study describes the clinical trial leading to first approval of talazoparib.
LaFargue, C. J., Dal Molin, G. Z., Sood, A. K. & Coleman, R. L. Exploring and comparing adverse events between PARP inhibitors. Lancet Oncol. 20, e15–e28 (2019).
Murthy, P. & Muggia, F. PARP inhibitors: clinical development, emerging differences and the current therapeutic issues. Cancer Drug Resist. 2, 665–679 (2019).
Adashek, J. J., Jain, R. K. & Zhang, J. Clinical development of PARP inhibitors in treating metastatic castrate-resistant prostate cancer. Cells 8, 860 (2019).
Golan, T. et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381, 317–327 (2019).
Pujade-Lauraine, E. et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 1274–1284 (2017).
Moore, K. et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 379, 2495–2505 (2018).
Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).
Ramalingam, S. S. et al. Randomized, placebo-controlled, phase II study of veliparib in combination with carboplatin and paclitaxel for advanced/metastatic non-small cell lung cancer. Clin. Cancer Res. 23, 1937–1944 (2017).
Shen, Y., Aoyagi-Scharber, M. & Wang, B. Trapping poly(ADP-ribose) polymerase. J. Pharmacol. Exp. Ther. 353, 446–457 (2015).
Kleinberg, L. et al. Phase I adult brain tumour consortium (ABTC) trial of ABT-888 (veliparib), temozolomide (TMZ) and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM) including pharmacokinetic (PK) data. J. Clin. Oncol. 31 (Suppl.15), 2065 (2013).
Mehta, M. P. et al. Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study. J. Neurooncol. 122, 409–417 (2015).
Su, J. M. et al. A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: a pediatric brain tumor consortium report. Neuro. Oncol. 16, 1661–1668 (2014).
Baxter, P. A. et al. A phase I/II clinical trial of veliparib (ABT-888) and radiation followed by maintenance therapy with veliparib and temozolomide in patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG): a pediatric brain tumor consortium interim report of phase I study. J. Clin. Oncol. 33 (Suppl. 15), 10053 (2015).
Lickliter, J. D. et al. A phase I dose-escalation study of BGB-290, a novel PARP1/2 selective inhibitor in patients with advanced solid tumors. J. Clin. Oncol. 34 (Suppl. 15), e17049 (2016).
Friedlander, M. et al. Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial. Lancet Oncol. 20, 1306–1315 (2019).
Luo, J. et al. Fluzoparib increases radiation sensitivity of non-small cell lung cancer (NSCLC) cells without BRCA1/2 mutation, a novel PARP1 inhibitor undergoing clinical trials. J. Cancer Res. Clin. Oncol. 146, 721–737 (2020).
Xu, J. M. et al. Phase I study of fluzoparib, a PARP1 inhibitor in combination with apatinib and paclitaxel in patients (pts) with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. J. Clin. Oncol. 37 (Suppl. 15), 4060 (2019).
Gupta, S. K. et al. PARP inhibitors for sensitization of alkylation chemotherapy in glioblastoma: impact of blood-brain barrier and molecular heterogeneity. Front. Oncol. 8, 670 (2019).
Kizilbash, S. H. et al. Restricted delivery of talazoparib across the blood-brain barrier limits the sensitizing effects of PARP inhibition on temozolomide therapy in glioblastoma. Mol. Cancer Ther. 16, 2735–2746 (2017).
Durmus, S. et al. Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) restrict oral availability and brain accumulation of the PARP inhibitor rucaparib (AG-014699). Pharm. Res. 32, 37–46 (2015).
Ding, L. et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 25, 2972–2980.e5 (2018).
Shen, J. et al. PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res. 79, 311–319 (2019). This study demonstrates the therapeutic potential of a PARP inhibitor in combination with immune checkpoint blockade.
Stewart, R. A., Pilié, P. G. & Yap, T. A. Development of PARP and immune-checkpoint inhibitor combinations. Cancer Res. 78, 6717–6725 (2018).
Lee, E. K. & Konstantinopoulos, P. A. Combined PARP and immune checkpoint inhibition in ovarian cancer. Trends Cancer 5, 524–528 (2019).
Wilson, R. H. et al. A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours. Br. J. Cancer 116, 884–892 (2017).
Cree, I. A. & Charlton, P. Molecular chess? Hallmarks of anti-cancer drug resistance. BMC Cancer 17, 10 (2017).
Sakai, W. et al. Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer Res. 69, 6381–6386 (2009). This study identifies secondary mutations in BRCA2 that restore BRCA2 function.
Norquist, B. et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J. Clin. Oncol. 29, 3008–3015 (2011).
Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).
Hurley, R. M. et al. 53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer. Gynecol. Oncol. 153, 127–134 (2019).
Xu, G. et al. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature 521, 541–544 (2015).
Patel, A. G., Sarkaria, J. N. & Kaufmann, S. H. Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc. Natl Acad. Sci. USA 108, 3406–3411 (2011).
Chaudhuri, R. A. et al. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535, 382–387 (2016).
Gogola, E. et al. Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality. Cancer Cell 33, 1078–1093 (2018).
Ibrahim, Y. H. et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2, 1036–1047 (2012).
Juvekar, A. et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2, 1048–1063 (2012).
Mukhopadhyay, A., Drew, Y., Matheson, E. et al. Evaluating the potential of kinase inhibitors to suppress DNA repair and sensitise ovarian cancer cells to PARP inhibitors. Biochem. Pharmacol. 167, 125–132 (2019).
Roos, W. P. & Krumm, A. The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair. Nucleic Acids Res. 44, 10017–10030 (2016).
Peasland, A. et al. Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. Br. J. Cancer 105, 372–381 (2011). This is the first article to show synergy between PARP inhibitors and ATR inhibitors.
Yazinski, S. A. et al. ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev. 31, 318–332 (2017).
Pilié, P. G., Gay, C. M., Byers, L. A., O’Connor, M. J. & Yap, T. A. PARP inhibitors: extending benefit beyond BRCA-mutant cancers. Clin. Cancer Res. 25, 3759–3771 (2019).
Haynes, B., Murai, J. & Lee, J. M. Restored replication fork stabilization, a mechanism of PARP inhibitor resistance, can be overcome by cell cycle checkpoint inhibition. Cancer Treat. Rev. 71, 1–7 (2018).
Johnson, N. et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat. Med. 17, 875–883 (2011).
Pacher, P. & Szabo, C. Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. Am. J. Pathol. 173, 2–13 (2008).
Curtin, N. J. & Szabo, C. Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol. Asp. Med. 34, 1217–1256 (2013).
Szabó, C. & Dawson, V. L. Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol. Sci. 19, 287–298 (1998).
Virág, L. & Szabó, C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol. Rev. 54, 375–429 (2002).
Jagtap, P. & Szabó, C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat. Rev. Drug Discov. 4, 421–440 (2005).
Giansanti, V., Donà, F., Tillhon, M. & Scovassi, A. I. PARP inhibitors: new tools to protect from inflammation. Biochem. Pharmacol. 80, 1869–1877 (2010).
Bai, P. & Virág, L. Role of poly(ADP-ribose) polymerases in the regulation of inflammatory processes. FEBS Lett. 586, 3771–3777 (2012).
García, S. & Conde, C. The role of poly(ADP-ribose) polymerase-1 in rheumatoid arthritis. Mediators Inflamm. 2015, 837250 (2015).
Henning, R. J., Bourgeois, M. & Harbison, R. D. Poly(ADP-ribose) polymerase (PARP) and PARP inhibitors: mechanisms of action and role in cardiovascular disorders. Cardiovasc. Toxicol. 18, 493–506 (2018).
Dawson, T. M. & Dawson, V. L. Nitric oxide signaling in neurodegeneration and cell death. Adv. Pharmacol. 82, 57–83 (2018).
Halmosi, R. et al. PARP inhibition and postinfarction myocardial remodeling. Int. J. Cardiol. 217, S52–S59 (2016).
Tapodi, A. et al. PARP inhibition induces Akt-mediated cytoprotective effects through the formation of a mitochondria-targeted phospho-ATM-NEMO-Akt-mTOR signalosome. Biochem. Pharmacol. 162, 98–108 (2019).
Zingarelli, B., Salzman, A. L. & Szabo, C. Genetic disruption of poly (ADP ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia-reperfusion injury. Circ. Res. 83, 85–94 (1998).
Liaudet, L. et al. Suppression of poly (ADP-ribose) polymerase activation by 3-aminobenzamide in a rat model of myocardial infarction: long-term morphological and functional consequences. Br. J. Pharmacol. 133, 1424–1430 (2001).
Tóth-Zsámboki, E. et al. Activation of poly(ADP-ribose) polymerase by myocardial ischemia and coronary reperfusion in human circulating leukocytes. Mol. Med. 12, 221–228 (2006). This study provides the first evidence in humans that PARP is activated in myocardial infarction.
Khan, T. A. et al. Poly(ADP-ribose) polymerase inhibition improves postischemic myocardial function after cardioplegia-cardiopulmonary bypass. J. Am. Coll. Surg. 197, 270–277 (2003).
Xiao, C. Y., Chen, M., Zsengellér, Z. & Szabo, C. Poly(ADP-ribose) polymerase contributes to the development of myocardial infarction in diabetic rats and regulates the nuclear translocation of apoptosis-inducing factor. J. Pharmacol. Exp. Ther. 310, 498–504 (2004).
Szabó, G. et al. Poly(ADP-ribose) polymerase inhibition attenuates biventricular reperfusion injury after orthotopic heart transplantation. Eur. J. Cardiothorac. Surg. 27, 226–234 (2005).
Roesner, J. P. et al. Therapeutic injection of PARP inhibitor INO-1001 preserves cardiac function in porcine myocardial ischemia and reperfusion without reducing infarct size. Shock 33, 507–512 (2010).
Szabo, C., Biser, A., Benko, R., Böttinger, E. & Suszták, K. Poly(ADP-ribose) polymerase inhibitors ameliorate nephropathy of type 2 diabetic Lepr db/db mice. Diabetes 55, 3004–3012 (2006).
Xiao, C. Y. et al. Poly(ADP-ribose) polymerase promotes cardiac remodeling, contractile failure, and translocation of apoptosis-inducing factor in a murine experimental model of aortic banding and heart failure. J. Pharmacol. Exp. Ther. 312, 891–898 (2005).
Clark, R. S. et al. Local administration of the poly(ADP-ribose) polymerase inhibitor INO-1001 prevents NAD+ depletion and improves water maze performance after traumatic brain injury in mice. J. Neurotrauma 24, 1399–1405 (2007).
d’Avila, J. C. et al. Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor. J. Neuroinflammation 9, 31 (2012).
Cardinale, A., Paldino, E., Giampà, C., Bernardi, G. & Fusco, F. R. PARP-1 inhibition is neuroprotective in the R6/2 mouse model of Huntington’s disease. PLoS ONE 10, e0134482 (2015).
Morrow, D. A. et al. A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial. J. Thromb. Thrombolysis 27, 359–364 (2009). This study is the first clinical trial of a PARP inhibitor in a non-oncological indication (myocardial infarction).
Bedikian, A. Y. et al. A phase IB trial of intravenous INO-1001 plus oral temozolomide in subjects with unresectable stage-III or IV melanoma. Cancer Invest. 27, 756–763 (2009).
Kim, Y. et al. Early treatment with poly(ADP-ribose) polymerase-1 inhibitor (JPI-289) reduces infarct volume and improves long-term behavior in an animal model of ischemic stroke. Mol. Neurobiol. 55, 7153–7163 (2018).
Noh, M. Y. et al. Regulatory T cells increase after treatment with poly (ADP-ribose) polymerase-1 inhibitor in ischemic stroke patients. Int. Immunopharmacol. 60, 104–110 (2018).
Bracken, C. et al. Inhibition of PARP1 attenuates rat renal ischemia reperfusion injury. J. Am. Soc. Nephrol. 29 (Suppl.), 882 Abstr. SA-PO561 (2018).
Feng, F. Y., de Bono, J. S., Rubin, M. A. & Knudsen, K. E. Chromatin to clinic: the molecular rationale for PARP1 inhibitor function. Mol. Cell 58, 925–934 (2015).
Berger, N. A. et al. Opportunities for the repurposing of PARP inhibitors for the therapy of non-oncological diseases. Br. J. Pharmacol. 175, 192–222 (2018).
Olsen, A. L. & Feany, M. B. PARP inhibitors and Parkinson’s disease. N. Engl. J. Med. 380, 492–494 (2019).
Choi, S. K. et al. Poly(ADP-ribose) polymerase 1 inhibition improves coronary arteriole function in type 2 diabetes mellitus. Hypertension 59, 1060–1068 (2012).
Mouchiroud, L. et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013).
Pirinen, E. et al. Pharmacological inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle. Cell Metab. 19, 1034–1041 (2014).
Ghonim, M. A. et al. PARP inhibition by olaparib or gene knockout blocks asthma-like manifestation in mice by modulating CD4+ T cell function. J. Transl. Med. 13, 225 (2015).
Xu, J. C. et al. Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity. Sci. Transl. Med. 8, 333ra48 (2016).
Rom, S. et al. PARP inhibition in leukocytes diminishes inflammation via effects on integrins/ cytoskeleton and protects the blood-brain barrier. J. Neuroinflammation 13, 254 (2016).
Fang, E. F. et al. NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24, 566–581 (2016).
Sahaboglu, A. et al. Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration. Sci. Rep. 6, 39537 (2016).
Vidal-Gil, L., Sancho-Pelluz, J., Zrenner, E., Oltra, M. & Sahaboglu, A. Poly ADP ribosylation and extracellular vesicle activity in rod photoreceptor degeneration. Sci. Rep. 9, 3758 (2019).
Jang, K. H. et al. AIF-independent parthanatos in the pathogenesis of dry age-related macular degeneration. Cell Death Dis. 8, e2526 (2017).
Trakkides, T. O. et al. Oxidative stress increases endogenous complement-dependent inflammatory and angiogenic responses in retinal pigment epithelial cells independently of exogenous complement sources. Antioxidants 8, 548 (2019).
Gariani, K. et al. Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease. J. Hepatol. 66, 132–141 (2017).
Korkmaz-Icöz, S. et al. Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats. Br. J. Pharmacol. 175, 246–261 (2018).
McGurk, L. et al. Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 6, 84 (2018).
Krainz, T. et al. Synthesis and evaluation of a mitochondria-targeting poly(ADP-ribose) polymerase-1 inhibitor. ACS Chem. Biol. 13, 2868–2879 (2018).
Tajuddin, N., Kim, H. Y. & Collins, M. A. PARP inhibition prevents ethanol-induced neuroinflammatory signaling and neurodegeneration in rat adult-age brain slice cultures. J. Pharmacol. Exp. Ther. 365, 117–126 (2018).
Ahmad, A. et al. The PARP inhibitor olaparib exerts beneficial effects in mice subjected to cecal ligature and puncture and in cells subjected to oxidative stress without impairing DNA integrity: A potential opportunity for repurposing a clinically used oncological drug for the experimental therapy of sepsis. Pharmacol. Res. 145, 104263 (2019).
Ahmad, A. et al. Effects of the poly(ADP-ribose) polymerase inhibitor olaparib in cerulein-induced pancreatitis. Shock 53, 653–665 (2020).
Zhang, D. et al. DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation. Nat. Commun. 10, 1307 (2019).
Nagy, L. et al. Olaparib induces browning of in vitro cultures of human primary white adipocytes. Biochem. Pharmacol. 167, 76–85 (2019).
Lee, Y. et al. Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat. Neurosci. 16, 1392–1400 (2013).
Teng, F. et al. Neuroprotective effects of poly(ADP-ribose)polymerase inhibitor olaparib in transient cerebral ischemia. Neurochem. Res. 41, 1516–1526 (2016).
Kapoor, K., Singla, E., Sahu, B. & Naura, A. S. PARP inhibitor, olaparib ameliorates acute lung and kidney injury upon intratracheal administration of LPS in mice. Mol. Cell Biochem. 400, 153–162 (2015).
Ghonim, M. A. et al. PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice. Clin. Sci. 129, 951–962 (2015).
Mukhopadhyay, P. et al. PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. J. Hepatol. 66, 589–600 (2017).
Ahmad, A., Olah, G., Herndon, D. N. & Szabo, C. The clinically used PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in a murine model of third-degree burn injury. Br. J. Pharmacol. 175, 232–245 (2018).
McCullough, L. D., Zeng, Z., Blizzard, K. K., Debchoudhury, I. & Hurn, P. D. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J. Cereb. Blood Flow. Metab. 25, 502–512 (2005).
Charriaut-Marlangue, C. et al. Sex differences in the effects of PARP inhibition on microglial phenotypes following neonatal stroke. Brain Behav. Immun. 73, 375–389 (2018).
Mabley, J. G. et al. Gender differences in the endotoxin-induced inflammatory and vascular responses: potential role of poly(ADP-ribose) polymerase activation. J. Pharmacol. Exp. Ther. 315, 812–820 (2005). This is the first demonstration of sex differences in PARP activity, in an animal model of endotoxic shock.
Zaremba, T. et al. Poly(ADP-ribose) polymerase-1 (PARP-1) pharmacogenetics, activity and expression analysis in cancer patients and healthy volunteers. Biochem. J. 436, 671–679 (2011).
Di Girolamo, M. & Fabrizio, G. The ADP-ribosyl-transferases diphtheria toxin-like (ARTDs) family: an overview. Challenges 9, 24 (2018).
Qin, W. et al. Research progress on PARP14 as a drug target. Front. Pharmacol. 10, 1–12 (2019).
Obaji, E., Haikarainen, T. & Lehtiö, L. Structural basis for DNA break recognition by ARTD2/PARP2. Nucleic Acids Res. 46, 12154–12165 (2018).
Hanzlikova, H., Gittens, W., Krejcikova, K., Zeng, Z. & Caldecott, K. W. Overlapping roles for PARP1 and PARP2 in the recruitment of endogenous XRCC1 and PNKP into oxidized chromatin. Nucleic Acids Res. 45, 2546–2557 (2017).
Thomas, C., Ji, Y., Lodhi, N., Kotova, E., Pinnola, A. D., Golovine, K., Makhov, P., Pechenkina, K., Kolenko, V. & Tulin, A. V. Non-NAD-like poly(ADP-ribose) polymerase-1 inhibitors effectively eliminate cancer in vivo. EBioMedicine 13, 90–98 (2016).
Wang, Y. Q. et al. An update on poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors: opportunities and challenges in cancer therapy. J. Med. Chem. 59, 9575–9598 (2016).
Wahlberg, E. et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat. Biotechnol. 30, 283–288 (2012).
Thorsell, A. G. et al. Structural basis for potency and promiscuity in poly(ADP-ribose) polymerase (PARP) and tankyrase inhibitors. J. Med. Chem. 60, 1262–1271 (2017).
Sherstyuk, Y. V. et al. Design, synthesis and molecular modeling study of conjugates of ADP and morpholino nucleosides as a novel class of inhibitors of PARP-1, PARP-2 and PARP-3. Int. J. Mol. Sci. 21, E214 (2019).
Farrés, J. et al. PARP2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice. Blood 122, 44–54 (2013).
Ali, S. O., Khan, F. A., Galindo-Campos, M. A. & Yélamos, J. Understanding specific functions of PARP-2: new lessons for cancer therapy. Am. J. Cancer Res. 6, 1842–1863 (2016).
Popoff, I., Jijon, H., Monia, B., Tavernini, M., Ma, M., McKay, R. & Madsen, K. Antisense oligonucleotides to poly(ADP-ribose) polymerase-2 ameliorate colitis in interleukin-10-deficient mice. J. Pharmacol. Exp. Ther. 303, 1145–1154 (2002).
Kamboj, A. et al. Poly(ADP-ribose) polymerase 2 contributes to neuroinflammation and neurological dysfunction in mouse experimental autoimmune encephalomyelitis. J. Neuroinflammation 10, 49 (2013).
Lu, A. Z. et al. Enabling drug discovery for the PARP protein family through the detection of mono-ADP-ribosylation. Biochem. Pharmacol. 167, 97–106 (2019).
Hsiao, S. J. & Smith, S. Tankyrase function at telomeres, spindle poles, and beyond. Biochimie 90, 83–92 (2008).
Ye, J. Z. & de Lange, T. TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat. Genet. 36, 618–623 (2004).
Ferri, M. et al. Targeting Wnt-driven cancers: discovery of novel tankyrase inhibitors. Eur. J. Med. Chem. 142, 506 (2017).
Lehtiö, L., Chi, N. W. & Krauss, S. Tankyrases as drug targets. FEBS J. 280, 3576–3593 (2013).
Kamal, A., Riyaz, S., Srivastava, A. K. & Rahim, A. Tankyrase inhibitors as therapeutic targets for cancer. Curr. Top. Med. Chem. 14, 1967–1976 (2014).
Riffell, J. L., Lord, C. J. & Ashworth, A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat. Rev. Drug Discov. 11, 923–936 (2012).
Plummer, E. R. et al. First-in-human phase 1 study of the PARP/tankyrase inhibitor 2X-121 (E7449) as monotherapy in patients with advanced solid tumors and validation of a novel drug response predictor (DRP) mRNA biomarker. J. Clin. Oncol. 36, S2505 (2018).
Rodriguez-Vargas, J. M., Nguekeu-Zebaze, L. & Dantzer, F. PARP3 comes to light as a prime target in cancer therapy. Cell Cycle 18, 1295–1301 (2019).
Beck, C., Robert, I., Reina-San-Martin, B., Schreiber, V. & Dantzer, F. Poly(ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3. Exp. Cell Res. 329, 18–25 (2014).
Lindgren, A. E. et al. PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3. ACS Chem. Biol. 8, 1698–1703 (2013).
Sharif-Askari, B., Amrein, L., Aloyz, R. & Panasci, L. PARP3 inhibitors ME0328 and olaparib potentiate vinorelbine sensitization in breast cancer cell lines. Breast Cancer Res. Treat. 172, 23–32 (2018).
Brunyanszki, A., Szczesny, B., Virág, L. & Szabo, C. Mitochondrial poly(ADP-ribose) polymerase: the Wizard of Oz at work. Free Radic. Biol. Med. 100, 257–270 (2016).
Maciag, A. E. et al. Nitric oxide (NO) releasing poly ADP-ribose polymerase 1 (PARP-1) inhibitors targeted to glutathione S-transferase P1-overexpressing cancer cells. J. Med. Chem. 57, 2292–2302 (2014).
Gallyas, F. Jr, Sumegi, B. & Szabo, C. Role of Akt activation in PARP inhibitor resistance in cancer. Cancers 12, 532 (2020).
Bonfiglio, J. J. et al. Serine ADP-ribosylation depends on HPF1. Mol. Cell 65, 932–940 (2017).
Gibbs-Seymour, I., Fontana, P., Rack, J. G. M. & Ahel, I. HPF1/C4orf27 is a PARP-1-interacting protein that regulates PARP-1 ADP-ribosylation activity. Mol. Cell 62, 432–442 (2016).
Bartlett, E. et al. Interplay of histone marks with serine ADP-ribosylation. Cell Rep. 24, 3488–3502 (2018).
Han, W., Li, X. & Fu, X. The macro domain protein family: structure, functions, and their potential therapeutic implications. Mutat. Res. 727, 86–103 (2011).
Barkauskaite, E., Jankevicius, G., Ladurner, A. G., Ahel, I. & Timinszky, G. The recognition and removal of cellular poly(ADP-ribose) signals. FEBS J. 280, 3491–3507 (2013).
Krietsch, J. et al. Reprogramming cellular events by poly(ADP-ribose)-binding proteins. Mol. Aspects Med. 34, 1066–1087 (2013).
Rack, J. G., Perina, D. & Ahel, I. Macrodomains: structure, function, evolution, and catalytic activities. Annu. Rev. Biochem. 85, 431–454 (2016).
Jonsson, P. et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature 571, 576–579 (2019).
Curtin, N. J., Drew, Y. & Sharma-Saha, S. Why BRCA mutations are not tumour-agnostic biomarkers for PARP inhibitor therapy. Nat. Rev. Clin. Oncol. 16, 725–726 (2019).
New REF Gentles, L. et al. Exploring the frequency of homologous recombination DNA repair dysfunction in multiple cancer types. Cancers 11, 354 (2019).
Patterson, M. J. et al. Assessing the function of homologous recombination DNA repair in malignant pleural effusion (MPE) samples. Br. J. Cancer 111, 94–100 (2014).
Alves-Lopes, R. & Touyz, R. M. Poly(ADP-ribose) polymerase-1 (PARP-1) - a novel target in aortic aneurysm. Hypertension 72, 1087–1089 (2018).
Sahaboglu, A. et al. Drug repurposing studies of PARP inhibitors as a new therapy for inherited retinal degeneration. Cell. Mol. Life Sci. 77, 2199–2216 (2020).
Rao, P. D. et al. ‘PARP’ing fibrosis: repurposing poly (ADP-ribose) polymerase (PARP) inhibitors. Drug Discov. Today https://doi.org/10.1016/j.drudis.2020.04.019 (2020).
Curtin, N. et al. Repositioning PARP inhibitors for SARS-CoV-2 infection (COVID-19); a new multi-pronged therapy for ARDS? Br. J. Pharmacol. https://doi.org/10.1111/bph.15137 (2020).
Szabo, C., Martins, V. & Liaudet, L. Poly(ADP-ribose) polymerase inhibition in acute lung injury: a re-emerging concept. Am. J. Respir. Cell. Mol. Biol. https://doi.org/10.1165/rcmb.2020-0188TR (2020).
Acknowledgements
The research of N.J.C. in the field of PARP has been supported by grants from Cancer Research UK, Cancer Research UK Development Committee, the Association for International Cancer Research (06-0031), the Biotechnology and Biological Sciences Research Council, the Bone Cancer Research Trust, the JGW Patterson Foundation, Newcastle Healthcare Charity, the Northern Cancer Care & Research Society, the Academy of Medical Sciences (NIF\R1\181894) and the UK–India Education and Research Initiative/British Council (DST/INT/UK/P-134/2016). The research of C.S. in the field of PARP is supported by grants from the Swiss National Foundation (31003A_179434) and the Swiss State Secretariat for Education, Research and Innovation (SMG1927).
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding authors
Ethics declarations
Competing interests
C.S. has no conflicts of interest to declare. N.C. has served on the scientific advisory boards of various companies making PARP inhibitors (AbbVie, BioMarin, Eisai and Tesaro) and other DNA damage response inhibitors (Sierra). She has received royalty payments from the commercial development of Rubraca, which have been used to fund her group’s research and to establish the Curtin PARP (Passionate About Realizing your Potential) Fund at the Community Foundation (UK). Her PARP-related work has been supported by funding from Agouron Pharmaceuticals, Pfizer, Clovis, BioMarin and BiPar Sciences.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Curtin, N.J., Szabo, C. Poly(ADP-ribose) polymerase inhibition: past, present and future. Nat Rev Drug Discov 19, 711–736 (2020). https://doi.org/10.1038/s41573-020-0076-6
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41573-020-0076-6
This article is cited by
-
Small cell lung cancer: emerging subtypes, signaling pathways, and therapeutic vulnerabilities
Experimental Hematology & Oncology (2024)
-
Application of PARP inhibitors combined with immune checkpoint inhibitors in ovarian cancer
Journal of Translational Medicine (2024)
-
Comprehensive machine learning boosts structure-based virtual screening for PARP1 inhibitors
Journal of Cheminformatics (2024)
-
Impact of PARP inhibitors on progression-free survival in platinum-sensitive recurrent epithelial ovarian cancer: a retrospective analysis
World Journal of Surgical Oncology (2024)
-
HBV DNA polymerase upregulates the transcription of PD-L1 and suppresses T cell activity in hepatocellular carcinoma
Journal of Translational Medicine (2024)