Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond

Abstract

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 (HRR) repair 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.

Poly(ADP-ribose) polymerases as modulators of mitochondrial activity

“…Highly selective PARP inhibitors are in clinical trials to combat neoplasms through impairing DNA repair processes in these cells [80]; however, a large body of evidence suggests that PARP inhibitors can have anti-Warburg properties as well [81]. PARP activation suppresses the mitochondrial oxidation [16] that is common with Warburg-type metabolism, while PARP inhibition induces mitochondrial activity [44,48], which is an anti-Warburg feature.…”

Insights into PARP Inhibitors’ Selectivity Using Fluorescence Polarization and Surface Plasmon Resonance Binding Assays

“…3,4 As the clinical trials with PARP inhibitors are in progress, the interest in understanding the extent of their cross-reactivity with other members of the ARTD family increases, especially in view of long-term therapies. 5,6 PARP inhibitors are generally designed to compete with NAD + at the enzyme active site; therefore, they have the potential to inhibit different members of the ARTD family or other enzymes that use NAD + as substrate. 6 Indeed, the most advanced inhibitors are highly potent on both PARP-1 and PARP-2, due to the high structural homology of their catalytic domains (69% sequence similarity).…”

Targeting DNA Repair Mechanisms to Treat Glioblastoma

“…It follows that interfering with DNA repair will enhance DNA damaging treatments. A number of preclinical studies confirm that PARP inhibition strengthens the efficacy of several DNA damaging anticancer therapies including radiation, DNA methylating agents, and topoisomerase I inhibitors [87]. A particu-larly exciting application of PARP inhibition is in cancer cells with defects in homologous recombination.…”

“…This example of synthetic lethality demonstrates that these two loss-of-function mutations prove fatal, whereas either mutation alone is not. Clinical trials have utilized PARP inhibitors in two ways: in combination with DNA damaging therapies and as a single agent for tumors deficient in homologous repair (e.g., BRCA1/2 mutated breast cancers) [87]. Further, epidermal growth factor receptor (EGFR) status may act as a predictive biomarker for PARP inhibition sensitivity [89].…”