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Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond
Open accessAbstract
The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination repair (HRR) is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. Multiple lines of preclinical data demonstrate that PARP inhibition increases cytotoxicity and tumor growth delay in combination with temozolomide, topoisomerase inhibitors and ionizing radiation. Both single agent and combination clinical trials are underway. The final part of the first section of the present review summarizes the current status of the various PARP inhibitors that are in various stages of clinical development. The second section of the present review summarizes the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock and acute myocardial infarction) the clinical translatability of PARP inhibition is supported by multiple lines of preclinical data, as well as observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well.
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“PARP inhibitors (Paribs) already exist and are clinically tested in the cancer field (Curtin and Szabo, 2013).”
From Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle (2014) · cites this paper as Curtin and Szabo, 2013
In the citing paper
“specific pharmacological inhibitors of PARP1 efficiently delay parthanatos in multiple cell types, in vitro and in vivo [1, 669].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [669]
In the citing paper
“PARP1 inhibition by pharmacological or genetic interventions mediates robust cytoprotective effects in multiple animal models of disease [1, 669].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [669]
In the citing paper
“Paribs are currently being tested for oncology indications, with positive outcomes in tumors with dysfunctional homologous DNA recombination repair (Curtin and Szabo, 2013).”
From Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle (2014) · cites this paper as Curtin and Szabo, 2013
In the citing paper
“The success of Paribs is thought to rely on the high dependency of these cancer cells on PARP enzymes for DNA repair (Curtin and Szabo, 2013), but could also involve their capacity to reprogram cells towards oxidative metabolism (Bai et al., 2011).”
From Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle (2014) · cites this paper as Curtin and Szabo, 2013
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1 retracted
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Cited by
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Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680
Regulated necrosis: the expanding network of non-apoptotic cell death pathways
Berghe, T. V., Linkermann, A., Jouan-Lanhouet, S., Walczak, H., & Vandenabeele, P. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3737 · Cited by 1,735
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Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects
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Essential versus accessory aspects of cell death: recommendations of the NCCD 2015
Galluzzi, L., Bravo-San Pedro, J. M., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., et al. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.137 · Cited by 1,002
Metadata
- Authors
- Curtin, N. J., & Szabo, C.
- Affiliations
- Newcastle University (GB)
- Corresponding author
- Curtin, Nicola J.
- ORCID
- Curtin, Nicola J.
- Venue
- Molecular Aspects of Medicine
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 34
- Issue
- 6
- Pages
- 1217-1256
- ISSN
- 0098-2997 (ISSN-L)
- PMC
- PMC3657315
- OpenAlex
- W2017171454
- Cited by
- 369
- References
- 559
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 12 · 2023: 22 · 2022: 25 · 2021: 25 · 2020: 37 · 2019: 31 · 2018: 26 · 2017: 32 · 2016: 38 · 2015: 50 · 2014: 24 · 2013: 21
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Aspects of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- PARP inhibitors, poly(ADP-ribose) polymerase, synthetic lethality, homologous recombination deficiency, BRCA mutations, breast cancer, ovarian cancer, temozolomide combination therapy, topoisomerase inhibitors, ionizing radiation, oxidative stress, nitrative stress, necrosis, inflammation, stroke, neurotrauma, shock, acute myocardial infarction, clinical translation
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Animals, Antineoplastic Agents, Cardiovascular Diseases, Clinical Trials as Topic, Enzyme Inhibitors, Humans, Neoplasms, Poly(ADP-ribose) Polymerases, Radiation-Sensitizing Agents, Stroke, Translational Research, Biomedical, Molecular Targeted Therapy
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