Clinical perspectives of PARP inhibitors

doi:10.1016/j.phrs.2005.02.013

Pharmacological Research

Volume 52, Issue 1, July 2005, Pages 109-118

https://doi.org/10.1016/j.phrs.2005.02.013 Get rights and content

Abstract

Poly(ADP-ribose) polymerase (PARP) activation plays a role in the pathogenesis of various cardiovascular and inflammatory diseases. At the same time, PARP activation is also relevant for the ability of cells to repair injured DNA. Thus, depending on the circumstances, pharmacological inhibitors of PARP may be able to attenuate ischemic and inflammatory cell and organ injury or may be able to enhance the cytotoxicity of antitumor agents. Both aspects of the “double-edged sword” role of PARP can be exploited for the experimental therapy of disease. As several classes of PARP inhibitors move towards clinical development, or have already entered the stage of clinical trials, we expect that in the upcoming few years, clinical proof of PARP inhibitors’ therapeutic effect will be obtained in human disease. In the current short overview, we summarize the pros and cons and challenges with respect to the clinical use of PARP inhibitors, the expected clinical outcomes and potential risks. It appears that on the cytoprotective aspect of PARP, acute, life-threatening diseases (myocardial infarction, cardiopulmonary bypass in high-risk patients, and other, severe forms of ischemia-reperfusion to other organs including stroke and thoracoabdominal aneurysm repair) may represent some of the prime development indications. In the context of inhibition of DNA repair, combination of PARP inhibitors with certain antitumor agents (for example temozolomide) in patients with tumors with extremely poor prognosis are expected to provide the initial clinical results. Development of PARP inhibitors for additional indications (e.g. chronic use for the therapy of neurodegeneration and neuroinflammation, or diabetic complications) may be more challenging because of the unknown potential long-term side effects of PARP inhibitors.

Section snippets

The double-edged sword role of PARP in regulating cell death

The role of PARP in the regulation of cell death has been a subject of intensive investigations over the last decade (overviewed in [1], [2], [3], [4], [5]). The first role of PARP-1 in cell death has been recognized as a “death substrate”. This particular role of PARP is based on the fact that it was one of the first identified substrates of caspases (cysteinyl aspartate-specific proteases), the main executioners of apoptosis. During apoptosis caspase-7 and caspase-3 cleave PARP-1 into two

Use of PARP inhibitors as sensitizing agents for anti-cancer therapies

Due to the involvement of PARP-1 and PARP-2 in the repair of DNA damage induced by certain anticancer agents [16], [17] or radiation, PARP inhibitors have been investigated as chemo- and radiosensitizers for cancer treatment.

Preclinical in vivo studies demonstrated that PARP inhibition is a suitable strategy to enhance the efficacy of the methylating agent temozolomide (TMZ), an anticancer drug recently approved for the treatment of recurrent high grade gliomas and currently investigated for

Use of PARP inhibitors for cytoprotection in acute cardiovascular and neurological indications

As overviewed in other sections of the current special issue of Pharmacological Research, PARP inhibitors (or PARP-1 genetic deficiency) exerts marked protective effects in a variety of acute cardiovascular indications. These indications are predominantly associated with a severe acute burst of oxidants and free radicals, that can occur due to occlusion and sudden re-canalization of a blood vessel supplying an organ (such as in stroke or in myocardial infarction). Other ischemia-reperfusion

Use of PARP inhibitors for cytoprotection in chronic cardiovascular and neurological indications

As overviewed in reference [1] and also in other sections of the current special issue of Pharmacological Research, PARP inhibitors (or PARP-1 genetic deficiency) exerts marked protective effects in a variety of chronic indications. These indications range from cardiovascular diseases (such as chronic heart failure, and diabetic complications) to neurological diseases (including Parkinson's disease). When considering these indications, a variety of practical issues need to be considered (1)

Conclusions

Despite extensive work in the area of PARP over the last decade, and the multitude of indications for the pharmaceutical inhibition of PARP (including many severe, life-threatening indications), there are no drugs on the market. This slow progress is in contrast to many other areas of drug development, where identification of a novel target was followed by the emergence of approved and marketed drugs within 10 years or so (see the example of the selective COX-2 inhibitors, where such compounds

Acknowledgements

Between 1999 and 2005, work in the area of PARP and diabetes and cardiovascular disease was supported by R01 grants from the National Institutes of Health to C.S. The work performed in the area of PARP inhibitors and cancer was supported by grants from the Italian Ministry of Education and Research (“Fondo per gli Investimenti della Ricerca di Base” and “Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale” projects) to G.G.

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View full text

Clinical perspectives of PARP inhibitors

Abstract

Section snippets

The double-edged sword role of PARP in regulating cell death

Use of PARP inhibitors as sensitizing agents for anti-cancer therapies

Use of PARP inhibitors for cytoprotection in acute cardiovascular and neurological indications

Use of PARP inhibitors for cytoprotection in chronic cardiovascular and neurological indications

Conclusions

Acknowledgements

Mutat Res

Prog Biophys Mol Biol

Biochem Biophys Res Commun

J Biol Chem

Pharmacol Res

Pharmacol Res

Cancer Treat Rev

J Biol Chem

Blood

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Cancer Lett

Biochim Biophys Acta

DNA Repair (Amst)

Am J Pathol

The therapeutic potential of poly(ADP-ribose) polymerase inhibitors

Pharmacol Rev

Role of PARP under stress conditions: cell death or protection?

Neurochem Res

Poly(ADP-ribosyl)ation inhibitors: promising drug candidates for a wide variety of pathophysiologic conditions

Int J Cancer

Failure of poly(ADP-ribose) polymerase cleavage by caspases leads to induction of necrosis and enhanced apoptosis

Mol Cell Biol

PARP is important for genomic stability but dispensable in apoptosis

Genes Dev

Poly(ADP-ribose) synthetase activation mediates mitochondrial injury during oxidant-induced cell death

J Immunol

Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly(ADP-ribose) synthase

Proc Natl Acad Sci USA

Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia

Nat Med

Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion

Proc Natl Acad Sci USA