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    • NSAIDs induce gastrointestinal toxicity and evoke

    2024-04-25

    NSAIDs induce gastrointestinal toxicity and evoke Cy7 NHS ester (non-sulfonated) by decreasing the production of gastroprotective prostanoids and by redirecting the COX substrate AA into LT biosynthesis, thereby causing vasoconstriction in gastric mucosa and airways (Celotti and Laufer, 2001; Koeberle and Werz, 2015; Rainsford, 2007). Recruitment and activation of immune cells by LTs further enhances gastrointestinal injury and the severity of asthmatic reactions. Dually acting anti-inflammatory drugs that target COX and 5-LO were developed to circumvent this shunting phenomenon, and they seem to induce far less gastrointestinal complications than NSAIDs (Bertolini et al., 2001; Celotti and Laufer, 2001; Charlier and Michaux, 2003; Grosch et al., 2017; Leone et al., 2007; Meirer et al., 2014). Moreover, inhibition of two major pro-inflammatory pathways promises superior anti-inflammatory activity, possibly even in a synergistic manner because PGs and LTs potentiate inflammation (Kondeti et al., 2016). Dual COX/5-LO inhibitors are also considered as promising targets for anti-tumoral therapy because eicosanoid-driven inflammation fosters cancer initiation and progression by regulating mitogenic and apoptotic signaling pathways, inducing angiogenesis as well as promoting tumor cell invasion (Gautam et al., 2017). Of note, Wculek & Malanchi recently reported that LT formation in PMNL supports the lung colonization of metastasis-initiating breast cancer cells in mouse models (Wculek and Malanchi, 2015) thereby providing a mechanistic basis for the well-established pro-tumoral properties of 5-LO (Radmark et al., 2015a). Multiple classes of dual COX/5-LO inhibitors have been synthesized and thoroughly characterized in pre-clinical studies over the past two decades (Grosch et al., 2017; Leone et al., 2007). Many of them exhibited potent anti-inflammatory activities, were well tolerated and essentially devoid of gastrointestinal side effects (Kulkarni and Singh, 2008; Leone et al., 2007). Several of them entered clinical studies but neither has been approved so far. The interest of the pharmaceutical industry in the development of dual COX/5-LO inhibitors faded. On the one hand, the role of 5-LO in inflammation and immunoregulation had to be newly defined after specialized pro-resolving mediators (SPMs) were discovered as crucial factors driving resolution and regeneration (Serhan, 2014). Note that physiological levels of SPMs are not necessarily reduced by dual COX/5-LO inhibitors despite 5-LO/FLAP being possibly involved in SPM biosynthesis (Lehmann et al., 2015; Serhan, 2014). For example, a mixed extract containing baicalin and catechin, called flavocoxid, dually inhibits COX and 5-LO and decreased circulating PGE2 and LTB4 concentrations while increasing plasma levels of lipoxin A4 in septic mice (Bitto et al., 2012). On the other hand, a novel dual strategy was born with mPGES-1 emerging as promising drug target, namely the dual targeting of mPGES-1 and 5-LO product biosynthesis, the latter either through inhibition of 5-LO or FLAP (Koeberle et al., 2016; Koeberle and Werz, 2009, Koeberle and Werz, 2014, Koeberle and Werz, 2015). The two MAPEG enzymes mPGES-1 and FLAP share structural features (Ferguson et al., 2007; Sjogren et al., 2013) which might facilitate the development of small-sized drug-like scaffolds, as realized in BRP187 (Garscha et al., 2016) and described below in this section. Conclusively, inhibition of mPGES-1 and 5-LO/FLAP might provide access to an exceptional safe therapy of inflammation by selectively suppressing pro-inflammatory PGE2 and LT formation without inhibiting the synthesis of homeostatic prostanoids. Licofelone reached clinical phase III for the therapy of osteoarthritis and is thus the most advanced dual anti-inflammatory drug, which targets multiple branches of eicosanoid biosynthesis (Kulkarni et al., 2002). It was first reported as dual COX/5-LO inhibitor based on the inhibition of prostanoid and LT biosynthesis in cellular studies (Celotti and Laufer, 2001). mPGES-1, FLAP and COX-1 were later identified as major molecular targets (Fischer et al., 2007; Koeberle et al., 2008a). Although the single targets are only moderately inhibited, licofelone combines strong analgesic, anti-inflammatory, antithrombotic and anti-asthmatic activities, and induces less gastrointestinal damage than NSAIDs (Kulkarni et al., 2002). Whether the moderate inhibition of COX-1 contributes to the efficacy and safety of licofelone is still elusive. It is tempting to speculate that a partial inhibition of COX-1 might compensate for the redirection of PGH2 into other prostanoid biosynthetic pathways (PGD2, PGF2α, PGI2, TxA2) upon interference with mPGES-1. The magnitude and direction of such substrate shunting depends on the tissue-specific expression of PG synthases (Koeberle and Werz, 2015; Scholich and Geisslinger, 2006) and is not necessarily detrimental as discussed in Section 4 for the role of PGI2 in the cardiovascular system.