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    • NSAIDs induce gastrointestinal toxicity and evoke asthma

    2023-03-03

    NSAIDs induce gastrointestinal toxicity and evoke PD 123319 ditrifluoroacetate 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.