NSAIDs——Sulindac Sulfide

General description

Sulindac sulfide is an aryl sulfide that is a metabolite of sulindac. A non-steroidal anti-inflammatory drug, which also has anticancer activity. It has a role as a non-steroidal anti-inflammatory drug, an apoptosis inducer and an antineoplastic agent. It is an aryl sulfide, an organofluorine compound and a monocarboxylic acid. It derives from a sulindac.

Figure1.NSAIDs’ effects on transcriptional factors. NSAIDs induce apoptosis through a variety of transcription factors and pathways. Protumorigenic proteins such as bcatenin, IjBa, and Sp1 are degraded by NSAIDs through ubiquitination pathways. NSAIDs can also induce ESE-1 nuclear translocation, where it binds to EGR-1’s promoter and up-regulates pro-apoptotic NAG-1 protein expression. ER stress is induced by NSAID treatment as well, which causes the ER membrane protein PERK to phosphorylate eIF2a. The phospho-eIF2a protein activates ATF4, which translocates to the nucleus where it binds to the promoter regions of the transcription factors CHOP or ATF3. This leads to up-regulation of CHOP and NAG-1. NSAIDs also induce apoptosis via unknown mechanisms. All of these pathways funnel into induction of apoptosis

Non-steroidal anti-inflammatory drugs (NSAIDs) are used extensively for analgesic and antipyretic treatments. In addition, NSAIDs reduce the risk and mortality to several cancers. Their mechanisms in antitumorigenesis are not fully understood, but both cyclooxygenase (COX)-dependent and independent pathways play a role. We and others have been interested in elucidating molecular targets of NSAID-induced apoptosis. In this review, we summarize updated literature regarding cellular and molecular targets modulated by NSAIDs. Among those NSAIDs, sulindac sulfide and tolfenamic acid are emphasized because these two drugs have been well investigated for their anti-tumorigenic activity in many different types of cancer.

Application and pharmacology

Sulindac Sulfide is the active metabolite of sulindac, a sulfinylindene derivative with anti-inflammatory, analgesic and antipyretic properties. Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) which inhibits cyclooxygenase (COX-1 and-2)-mediated conversion of arachidonic acid to pro-inflammatory prostaglandins. This agent may posulindac sulfideesulindac sulfide chemopreventive activity against colorectal tumors through a mechanism that involves the induction of apoptosis. The sulfide metabolite is excreted in the bile and reabsorbed from the intestine, thereby helping to maintain constant blood levels and reduce gastrointestinal side effects.[1]

The zinc-finger DNA binding protein early growth respose-1 (EGR-1) is involved in many activities including differentiation and tumorigenesis. EGR-1 acts as a tumor suppresulindac sulfideor in mouse two-step skin carcinogenesis using EGR-1 knock-out mice, and binds to the p53 promoter region bothin vitroandin vivo. Furthermore, EGR-1 plays an important role in up-regulating the expresulindac sulfideion of the anti-tumorigenic/pro-apoptotic protein NSAID activated gene-1 (NAG-1) and the anti-angiogenic protein thrombospondin-1 (TSP-1) in colorectal and lung cancer cells, respectively, during sulindac sulfide (SULINDAC SULFIDE) treatment[12,13]. NSAIDs upregulate EGR-1, which binds to the promoter regions of NAG-1 and TSP-1. This up-regulation has been confirmedin vivo, using a Sprague–Dawley rat model for early colorectal tumorigenesis, which uses the colon-specific pro-carcinogen 1,2-dimethylhydra-zine dihydrochloride (DMH)[14]. EGR-1 protein expresulindac sulfideion is induced in rats treated with sulindac or celecoxib, along with lesulindac sulfide tumor formation compared to control rats[14]. Another conventional NSAID, TA, also induces EGR-1 at the transcription level via enhancement of epithelium-specific ETS transcription factor-1 (ESE-1) nuclear translocation, which leads to activation of apoptosis in colorectal cancer cells.[2]

History

As early as ancient Egypt, it has been recorded that the bark and leaves of willow trees have analgesic effects. In 1763, it was reported that salicyliacid, an extract of willow bark, was used to treat arthritis. In 1860, Hoffman reported that "acetylsalicylic acid" was synthesized artificially. It marks the transformation of anti-inflammatory and analgesic drugs from plant drugs to chemical drugs. In 1899, acetylsalicylic acid was listed under the trade name of "aspirin" by Bayer company of Germany, and began to be used in clinical treatment of pain, arthritis and fever. In 1948, Since then, many NSAIDs with strong anti-inflammatory effects or low side effects have been listed, such as ibuprofen and indomethacin in the 1960s (indomethacin), diclofenac and naproxen in the 1970s, nabumetone and piroxicam in the 1980s, meloxicam and nimesulide in the mid-1990s, and celecoxib and rofecoxib in the late 1990s. From acetylsalicylic acid to rofecoxib, they have similar pharmacological characteristics, strong anti-inflammatory and analgesic effects and antipyretic effects in varying degrees. There are many kinds of NSAIDs, and their "family members" are still expanding. The goal of development is to pursue stronger anti-inflammatory and analgesic effects and / or higher safety. Some of them withdrew or faded out of the market due to side effects and other reasons. For example, butazone may cause aplastic anemia and is no longer used in clinic; The position of high-dose aspirin in the treatment of arthritis has also been replaced by non salicylic acid NSAIDs; Indomethacin is rarely used by orthopedics and rheumatologists because of gastrointestinal and central nervous system side effects; Rofecoxib withdrew from the market due to the hidden danger of cardiovascular and cerebrovascular diseases.[3]

Toxicity

The NSAID sulindac sulfide (SS) inhibits growth of tumors in azoxymethane-induced rat colon models, suppresulindac sulfidees intestinal polyp formation in APCMin+mice, down-regulatesβ-catenin protein apoptosis, and induces apoptosis under a number of experimental conditions. SULINDAC SULFIDE has been shown to change colorectal cancercell morphology, alter cytoskeletal organization, and cause losulindac sulfide of actin stresulindac sulfidefibers. This is probably due to a dose-dependent reduction of tyrosine phosphorylation of focal adhesion kinase. It has also been demonstrated that SULINDAC SULFIDE reduces cell migration and invasion in mouse models and human colorectal cell line[4]. Many, but not all, studies in healthy and diseased states suggest that renal prostaglandin synthesis and sodium excretion are relatively unaffected by conventional doses of sulindac that inhibit nonrenal cycle-oxygenase. The mechanism responsible for the biochemical selectivity of sulindac is not related to a differential sensitivity of the active metabolite of sulindac, sulindac sulfide, on renal cycle-oxygenase. Appropriate clinical use of all nonsteroidal anti-inflammatory drugs, including sulindac, requires careful consideration of risk factors that predispose to nephrotoxicity and careful monitoring when administered to patients at risk. 

Reference

1.Liggett J. L., Zhang X. & Eling T. E. et al., "Anti-tumor activity of non-steroidal anti-inflammatory drugs: Cyclooxygenase-independent targets," Cancer Letters, Vol.346, No.2(2014), pp.217-224.

2.Sedor J. R., Davidson E. W. & Dunn M. J., "Effects of nonsteroidal anti-inflammatory drugs in healthy subjects," The American journal of medicine, Vol.81, No.2B(1986), p.58.

3.Yang Xiuyan, Discussion on the comprehensive safety of non steroidal anti-inflammatory drugs from its history.

4.Liggett J. L., Choi C. K. & Donnell R. L. et al., "Nonsteroidal anti-inflammatory drug sulindac sulfide suppresses structural protein Nesprin-2 expression in colorectal cancer cells," Biochimica et Biophysica Acta (BBA) - General Subjects, Vol.1840, No.1(2014), pp.322-331.

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