Dose of 800 mg/day but not in the typical anti-inflammatory dose of 200 mg/day bid (23). The possibility that an off-target impact accounts for the chemopreventive activity of NSAIDs could as a result clarify their incomplete efficacy in clinical trials involving typical anti-inflammatory dosages. Possibly the strongest evidence for a COX-independent mechanism comes from experimental research showing that non-COX inhibitory metabolites (48), enantiomers (49) or derivatives (50) retain or have enhanced antitumor activity compared with the parent NSAID. Amongst these, the sulfone metabolite of sulindac, exisulind, could be the most studied, for which there’s an abundance of proof of efficacy from numerous rodent models of carcinogenesis (513), as summarized in Table 2. Figure 1 illustrates the metabolism of sulindac into the active sulfide kind as well as the non-COX-inhibitory sulfone. Also, exisulind has been reported to inhibit tumor cell development and induce apoptosis in numerous tumor types in spite of lacking COX-1 or COX-2 inhibitory activity (48). In studies involving the AOM model of rat colon tumorigenesis, exisulind inhibited tumor formation at dosages that did not cut down prostaglandin levels within the colon mucosa, and accomplished plasma concentrations above these essential to inhibit tumor cell development and induce apoptosis in vitro (52). In clinical trials, exisulind displayed substantial adenoma regression in patients with familial (54) or sporadic (55) adenomatous polyposis but didn’t obtain FDA approval resulting from hepatotoxicity and because of inherent difficulties with disease variation amongst FAP individuals that had been encountered during the registration trial. Nonetheless, its sturdy chemopreventive activity in preclinical models supports the value of COXindependent mechanisms as well as the rationale for creating other non-COX-inhibitory sulindac derivatives with improved potency and target selectivity.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptMolecular TargetsWhile an NSAID might act upon a COX-independent target with comparatively high specificity, it really is frequently recognized that a combinatorial action on various pathways by means of direct molecular targets too as epigenetic and post-transcriptional mechanisms is accountable for the chemopreventive properties of NSAIDs. Several of the major pathways targeted by NSAIDs are discussed beneath and illustrated in Table 3.Clin Cancer Res. Author manuscript; readily available in PMC 2015 March 01.Gurpinar et al.PageInduction of Apoptosis NSAIDs have extended been recognized to inhibit tumor cell development in cell culture models with significantly unique potencies across chemical families (56). The basis for this activity was first reported to involve apoptosis induction by two independent groups in 1995 (57, 58).NLRP1, Human The mechanism appeared to be unrelated to COX inhibition as evident by the ability of exisulind to also induce apoptosis.Ipilimumab Apoptosis emerged as the significant mechanism of NSAID chemoprevention following observations that therapy with sulindac can stimulate apoptosis in the regular rectal mucosa of FAP patients (59), normal intestinal mucosa of APCMin mice (60) and inside the colorectal carcinomas of carcinogen-treated rats (61).PMID:23291014 Furthermore, exisulind was reported to induce apoptosis in rectal polyps of FAP individuals but not in regular rectal mucosa, which implies an aspect of tumor selectivity (54). Consistent with these observations, studies employing cell culture models demonstrate that NSAIDs, as.