Clinical perspectives 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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