Apart from oncology preclinical efficacy

Apart from oncology, preclinical efficacy of PARP-1 inhibitors in mitigating inflammation, circulatory shock, myocardial infarction, and stroke likely results from the inhibition of PARP-1-mediated transcription activation (Curtin & Szabo, 2013). It has been shown that transcriptional profiles are dramatically altered by PARP-1 inhibition in innate immune signaling pathways, potentially dampening aberrant inflammatory activation (Gupte et al., 2015). So far, the introduction of these inhibitors beyond oncology has been hampered by the possible risks of toxicity and carcinogenesis, secondary to inhibiting an integral component of DNA repair (Maruyama et al., 1975). Therefore, finding inhibitors that are less cytotoxic and more selective toward PARP-1-mediated transcription would be of considerable clinical interest. However, the extent of PARP-1-mediated transcription in DNA repair is not entirely clear. Although it cannot be determined at this time whether these new inhibitors have a stronger predilection toward targeting PARP-1-mediated transcription, their antitumor potential and significant tegaserod cost in cytotoxicity could launch PARP-1 inhibitors further into other areas of molecular medicine.
Funding This research was supported by grants from the National Institutes of Health (R01 GM077452 and R01 DK082623) to A.V.T. The costs incurred for purchasing the subcollection of new PARP-1 inhibitors were partially covered by the Kahn\'s family gift to A.V.T. Funding agencies had no role in study design, data collection, data analysis, interpretation, writing of the report.
Conflict of Interest
Author Contributions
Acknowledgments
Introduction In 2012, 951,000 new gastric cancer (GC) cases and 723,000 deaths were estimated worldwide, making it the fifth most common tumor (Ferlay et al., 2015; Torre et al., 2015). GC is a complex disease arising from environmental and genetic factors. However in individuals infected with H. pylori, defined as a definite gastric carcinogen (Yang, 2006), only a few eventually develop into GC, which suggested that host genetic factors may play a crucial role in the susceptibility of GC (Saeki et al., 2013). The epigenetics is believed to be important in the development of cancers, which was defined as a stably heritable changes through modifying gene expression without DNA sequence alterations (Esteller, 2008). The most common epigenetic phenomenon is DNA methylation that refers to a methyl group is conferred to the 5′ carbon of a cytosine in a CpG dinucleotide. It is catalyzed by a family of DNA methyltransferases (DNMTs) mainly consisting of three activated forms: DNMT1, DNMT3A and DNMT3B. DNMT1 is thought to be a maintenance DNA methyltransferase which principally maintains CpG methylation, involving in embryonic development and somatic cells survival (Brown and Robertson, 2007) and it is encoded by DNMT1 gene which locates on chromosome 19p13.2 (Jiang et al., 2012a). DNMT3A and DNMT3B are considered as de novo methyltransferases which are required for the establishment of embryonic methylation patterns, mainly occurring during gametogenesis and early development (Okano et al., 1999) and they are encoded by DNMT3A and DNMT3B genes locating on chromosome 2p23 and 20q11.2 respectively (Yang et al., 2012). There is considerable evidence that a number of abnormal changes in single nucleotide polymorphisms (SNPs) of DNMTs (DNMT1, DNMT3A and DNMT3B), which could cause DNA hypo-methylation or hyper-methylation (Gao et al., 2011; Fu et al., 2010; Harder et al., 2008; Zhao and Bu, 2012), are correlated to tumor occurrence or decrease (Luo et al., 2015; Chang et al., 2014; Mostowska et al., 2013; Kullmann et al., 2013; Sun et al., 2012; Xiang et al., 2010; Kanai et al., 2003) such as head and neck cancer, and colorectal cancer (Zhu et al., 2015; Duan et al., 2015). However, the associations between DNMTs SNPs and GC risk were still conflicting (Jiang et al., 2012a; Yang et al., 2012). Therefore, for the first time, the effects of DNMTs polymorphisms on the susceptibility to GC were systematically and comprehensively estimated.