Abstract
Inhibitors of the nuclear DNA damage sensor and signalling enzyme poly(ADP-ribose) polymerase (PARP) have recently been introduced in the therapy of cancers deficient in double-strand DNA break repair systems, and ongoing clinical trials aim to extend their use from other forms of cancer non-responsive to conventional treatments. Additionally, PARP inhibitors were suggested to be repurposed for oxidative stress-associated non-oncological diseases resulting in a devastating outcome, or requiring acute treatment. Their well-documented mitochondria- and cytoprotective effects form the basis of PARP inhibitors’ therapeutic use for non-oncological diseases, yet can limit their efficacy in the treatment of cancers. A better understanding of the processes involved in their protective effects may improve the PARP inhibitors’ therapeutic potential in the non-oncological indications. To this end, we endeavoured to summarise the basic features regarding mitochondrial structure and function, review the major PARP activation-induced cellular processes leading to mitochondrial damage, and discuss the role of PARP inhibition-mediated mitochondrial protection in several oxidative stress-associated diseases.
Highlights
Inhibitors of the nuclear DNA damage sensor and signalling enzyme poly(ADP-ribose) (PAR) polymerase (PARP) have recently gained considerable interest in tumour therapy [1]
Heterodimerisation of pro-apoptotic members, such as B-cell lymphoma (Bcl)-2-associated X (Bax) and Bcl-2 homologous antagonist/killer (Bak), especially in the presence of Bcl-2 homology domain (BH)3-only proteins, such as Bcl-2-associated agonist of cell death (Bad), Bcl-2-like protein 11 (Bim), BH3 interacting-domain death agonist (Bid) and p53 upregulated modulator of apoptosis (PUMA) permeabilises the outer membrane via pore formation, which allows cytochrome C release from the mitochondrial intermembrane space leading to caspase-9 activation that eventually results in apoptotic cell death [71,72]
The intended extension of poly(ADP-ribose) polymerase (PARP) inhibitors in cancer therapy aims at the non-homologous recombination DNA repair systems, signalling pathways, angiogenesis, or immune checkpoint mechanisms, all utilising the function of PARP in DNA repair
Summary
Inhibitors of the nuclear DNA damage sensor and signalling enzyme poly(ADP-ribose) (PAR) polymerase (PARP) have recently gained considerable interest in tumour therapy [1]. Following the success of clinical trials, the United States Food and Drug Administration (FDA) approved four PARP inhibitors in the therapy of breast cancer gene (BRCA)1/2 mutated malignancies not responding to conventional treatments [2], and further trials are currently ongoing to extend their use to cancers carrying other forms of genomic instability [3]. Based on their cytoprotective properties demonstrated in many models, PARP inhibitors were suggested to be repurposed for non-oncological diseases such as acute pancreatitis, stroke, lung injury, traumatic brain injury, septic shock, and various degenerative diseases [4]. We summarised the basic features of mitochondrial structure and function, reviewed the major PARP activation-induced cellular processes leading to mitochondrial damage, and presented mechanistic aspects of PARP activation-induced mitochondrial damages in several oxidative stress-associated diseases
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