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  • br Materials and Methods br Ethics Statement

    2018-10-23


    Materials and Methods
    Ethics Statement
    Results
    Discussion Clinical interest in PARP-1 has increased over the past decade with the recognition of its roles in transcription regulation, DNA repair, epigenetic bookmarking, and selective serotonin reuptake inhibitors restructuring. Currently, over one hundred clinical studies are being carried out to evaluate PARP-1 inhibitors, most involving oncology (Feng et al., 2015). Given the initial promising results for treating certain types of cancer, the impetus is now focused on finding more effective and less cytotoxic PARP-1 inhibitors. Whereas the NAD-dependent route of PARP-1 activation has been exhaustively exploited for designing new inhibitors, the other two known routes of activation, namely, the histone H4- and DNA-dependent pathways, remain overlooked. Here we have reported the discovery of new PARP-1 inhibitors using a screen based on PARP-1 enzymatic activation via histone H4 (Passeri et al., 2015; Kotova et al., 2011b; Thomas et al., 2014). The screening for compounds inhibiting H4-induced PARP-1 activity also identified molecules similar in structure to NAD, including those acting like previously known PARP-1 inhibitors. Other inhibitors identified by the screen represent a new generation of PARP-1 inhibitors that are not NAD analogues. Because NAD is a crucial metabolic currency within cells, compounds that mimic NAD disrupt multiple cellular processes, leading to off-target effects. Therefore, novel non-NAD-like PARP-1 inhibitors are expected to possess minimal secondary toxicity, as they target an activation mechanism unique to the PARP-1 enzyme. Notably, the new non-NAD-like PARP-1 inhibitors demonstrate higher efficacy against several types of tumors compared to the classical NAD-like PARP-1 inhibitors. Activation of PARP-1 via histone H4 has been best described within the context of transcription regulation and changes in chromatin structure (Kotova et al., 2011b; Thomas et al., 2014). The expanse of histone-mediated PARP-1 activity, however, within the various known functions of PARP-1, e.g., DNA repair, is yet to be fully understood. The mechanism of action of these new- generation PARP-1 inhibitors is not clear and may involve several routes, e.g., obstructing PARP-1 interaction with H4 or provoking an inhibitory conformational change. Inhibiting allosteric regulation of PARP-1 has recently been shown to be another potential approach to the targeting of PARP-1 function (Steffen et al., 2014). When PARP-1 inhibitors were first evaluated for their potential in treating cancer, the underlying rationale for their application was to prevent PARP-1-mediated DNA repair, thereby reducing the survival potential of carcinogenic cells. Consequently, in oncology, PARP-1 inhibitors have been primarily tested either to increase the efficacy of cytotoxic therapies or as a monotherapy via synthetic lethality in tumors with already notable defective DNA repair pathways, namely homologous recombination. The synthetic lethality approach has been most extensively explored in BRCA1/2-deficient ovarian and breast cancers (Feng et al., 2015). The first PARP-1 inhibitor was recently approved by the FDA to treat ovarian cancer in women with BRCA1/2 mutations who had already failed three or more chemotherapy treatments. However, the responses to this therapeutic approach have been dramatically varied in patients with BRCA mutations, even including improved outcomes in cohorts of patients with wild-type BRCA genes (Duan et al., 2010; Ledermann et al., 2012; Ledermann et al., 2014). It has been speculated that PARP-1 inhibitor efficacy in oncology extends into its role in regulating transcription and chromatin structure (Maruyama et al., 1975). Maintaining an active chromatin state for transcribing genes is the central component in rapidly dividing cells (Lodhi et al., 2014), particularly those that are carcinogenic (Krishnakumar et al., 2008). It has also been shown that PARP-1 plays an integral role in transcription regulation of hormone-dependent cancers (Schiewer & Knudsen, 2014; Brenner et al., 2011). Overall, it seems clear that the role of PARP-1 inhibitors in oncology extends beyond initial experiments that targeted the role of PARPs in DNA repair.