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Current Opinion in Chemical Biology Oct 2023In the review, current status of sulfoxides on the pharmaceutical market is discussed. In the first part of the article, natural sulfoxides will be described with a... (Review)
Review
In the review, current status of sulfoxides on the pharmaceutical market is discussed. In the first part of the article, natural sulfoxides will be described with a special focus on sulforaphane and amanitin, a mushroom toxin which has been developed as payload in antibody drug conjugates in the possible cancer treatment. Controversies associated with the medical use of dimethylsulfoxide are briefly described in the next section. In the part devoted to PPIs, the benefits of using pure enantiomers (chiral switch) are discussed. An interesting approach, repositioning of drugs is exemplified by new possible applications of modafinil and sulindac. The review is concluded by presentation of cenicriviroc and adezmapimod, both with the status of promising drug candidates.
Topics: Sulfoxides; Dimethyl Sulfoxide; Stereoisomerism
PubMed: 37307682
DOI: 10.1016/j.cbpa.2023.102340 -
Cureus Aug 2022Colorectal carcinoma (CRC) is the most common of gastrointestinal cancers, the majority presenting with sporadic occurrence compared to the less frequently inherited... (Review)
Review
Colorectal carcinoma (CRC) is the most common of gastrointestinal cancers, the majority presenting with sporadic occurrence compared to the less frequently inherited syndromes. The increasing incidence, decreasing gender and age disparities, and the prevalent risk factors are concerning. The malignancy arising from benign precursor polyps transforms slowly over time. The adenoma variant polyps reported a marked upregulation of cyclooxygenases (COX), significantly COX-2 isoform, influenced by various determinants such as genetics, pathology, histology, and site of the carcinoma. These COX enzymes are responsible for prostaglandin synthesis and the consequent cascade of cell inflammation and proliferation. Therefore, COX inhibition by non-steroidal anti-inflammatory drugs (NSAIDs) targeted against both the isoforms COX-1 and COX-2 have been studied for decades in anticipation of preventing the occurrence of colorectal carcinoma in high-risk populations. This article has collated and highlighted the overexpression of COX enzymes by the adenomatous polyps and provides corroborating evidence from multiple studies in favor of COX inhibition by NSAIDs. Aspirin and Sulindac were two drugs to be initially proven to halt the progression and cause regression of the polyps. Celecoxib, a selective COX-2 inhibitor besides NSAIDs, was also used in experimental studies.
PubMed: 36185863
DOI: 10.7759/cureus.28579 -
Digestive Diseases (Basel, Switzerland) 2015Colorectal cancer has become one of the most prevalent malignant diseases for both men and women. Patients with inflammatory bowel diseases or certain inherited cancer... (Review)
Review
Colorectal cancer has become one of the most prevalent malignant diseases for both men and women. Patients with inflammatory bowel diseases or certain inherited cancer syndromes are at high risk of developing colorectal cancer and have naturally the highest need for cancer prevention. In familial adenomatous polyposis (FAP) and Lynch syndrome, most of the underlying germline mutations can be detected by DNA sequencing, and medical counselling of affected individuals involves both surveillance tests and chemopreventive measures. However, as the mechanisms leading to colorectal cancer differ in these high-risk groups, the molecular action of chemopreventive drugs needs to be adjusted to the certain pathway of carcinogenesis. In the last decades, a number of drugs have been tested, including sulindac, aspirin, celecoxib, and mesalazine, but some of them are still controversially discussed. This review summarizes the advances and current standards of colorectal cancer prevention in patients with inflammatory bowel disease, FAP and Lynch syndrome.
Topics: Anti-Inflammatory Agents; Chemoprevention; Colorectal Neoplasms; Dietary Supplements; Drug Therapy, Combination; Humans; Phytochemicals
PubMed: 25531498
DOI: 10.1159/000366037 -
Nature Communications Sep 2023Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in...
Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in the nervous system. Here, we utilized zebrafish larvae to assess the potentially toxic effects of nonsteroidal anti-inflammatory drugs and found that sulindac can selectively induce apoptosis of GABAergic neurons in the brains of zebrafish larvae brains. Zebrafish larvae exhibit hyperactive behaviour after sulindac exposure. We also found that akt1 is selectively expressed in GABAergic neurons and that SC97 (an Akt1 activator) and exogenous akt1 mRNA can reverse the apoptosis caused by sulindac. Further studies showed that sulindac binds to retinoid X receptor alpha (RXRα) and induces autophagy in GABAergic neurons, leading to activation of the mitochondrial apoptotic pathway. Finally, we verified that sulindac can lead to hyperactivity and selectively induce GABAergic neuron apoptosis in mice. These findings suggest that excessive use of sulindac may lead to early neurodevelopmental toxicity and increase the risk of hyperactivity, which could be associated with damage to GABAergic neurons.
Topics: Animals; Mice; Sulindac; Zebrafish; Apoptosis; Anti-Inflammatory Agents, Non-Steroidal; GABAergic Neurons; Larva
PubMed: 37660128
DOI: 10.1038/s41467-023-41114-y -
Acta Biochimica Et Biophysica Sinica Jan 2016Retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a well-established drug target, representing one of the most important targets... (Review)
Review
Retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a well-established drug target, representing one of the most important targets for pharmacologic interventions and therapeutic applications for cancer. However, how RXRα regulates cancer cell growth and how RXRα modulators suppress tumorigenesis are poorly understood. Altered expression and aberrant function of RXRα are implicated in the development of cancer. Previously, several studies had demonstrated the presence of N-terminally truncated RXRα (tRXRα) proteins resulted from limited proteolysis of RXRα in tumor cells. Recently, we discovered that overexpression of tRXRα can promote tumor growth by interacting with tumor necrosis factor-alpha-induced phosphoinositide 3-kinase and NF-κB signal transduction pathways. We also identified nonsteroidal anti-inflammatory drug Sulindac and analogs as effective inhibitors of tRXRα activities via a unique binding mechanism. This review discusses the emerging roles of tRXRα and modulators in the regulation of cancer cell survival and death as well as inflammation and our recent understanding of tRXRα regulation by targeting the alternate binding sites on its surface.
Topics: Animals; Apoptosis; Binding Sites; Cell Survival; Drug Discovery; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Ligands; Mice; NF-kappa B; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Binding; Protein Domains; Protein Multimerization; Retinoid X Receptor alpha; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 26494413
DOI: 10.1093/abbs/gmv104 -
Cancer Prevention Research... Aug 2022Obesity is associated with an increased risk of colon cancer. Our current study examines whether weight loss and/or treatment with the NSAID sulindac suppresses the...
UNLABELLED
Obesity is associated with an increased risk of colon cancer. Our current study examines whether weight loss and/or treatment with the NSAID sulindac suppresses the protumor effects of obesity in a mouse model of colon cancer. Azoxymethane-treated male FVB/N mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 15 weeks, then HFD mice were randomized to remain on HFD (obese) or switch to LFD [formerly obese (FOb-LFD)]. Within the control (LFD), obese, and FOb-LFD groups, half the mice started sulindac treatment (140 ppm in the diet). All mice were euthanized 7 weeks later. FOb-LFD mice had intermediate body weight levels, lower than obese but higher than control (P < 0.05). Sulindac did not affect body weight. Obese mice had greater tumor multiplicity and burden than all other groups (P < 0.05). Transcriptomic profiling indicated that weight loss and sulindac each modulate the expression of tumor genes related to invasion and may promote a more antitumor immune landscape. Furthermore, the fecal microbes Coprobacillus, Prevotella, and Akkermansia muciniphila were positively correlated with tumor multiplicity and reduced by sulindac in obese mice. Coprobacillus abundance was also decreased in FOb-LFD mice. In sum, weight loss and sulindac treatment, alone and in combination, reversed the effects of chronic obesity on colon tumor multiplicity and burden. Our findings suggest that an investigation regarding the effects of NSAID treatment on colon cancer risk and/or progression in obese individuals is warranted, particularly for those unable to achieve moderate weight loss.
PREVENTION RELEVANCE
Obesity is a colon cancer risk and/or progression factor, but the underlying mechanisms are incompletely understood. Herein we demonstrate that obesity enhances murine colon carcinogenesis and expression of numerous tumoral procancer and immunosuppressive pathways. Moreover, we establish that weight loss via LFD and/or the NSAID sulindac mitigate procancer effects of obesity.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Colonic Neoplasms; Diet, High-Fat; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Microbiota; Obesity; Sulindac; Transcriptome; Weight Loss
PubMed: 35653548
DOI: 10.1158/1940-6207.CAPR-21-0531 -
Best Practice & Research. Clinical... Aug 2011Familial adenomatous polyposis (FAP) predictably leads to adenomas and eventual adenocarcinomas in the lower gastrointestinal tract and less frequently, the upper... (Review)
Review
Familial adenomatous polyposis (FAP) predictably leads to adenomas and eventual adenocarcinomas in the lower gastrointestinal tract and less frequently, the upper gastrointestinal tract. Chemopreventive strategies have been studied in FAP patients to delay the development of adenomas in the upper and lower gastrointestinal tract, as well as to prevent recurrence of adenomas in the retained rectum of patients after prophylactic surgery with colectomy and ileorectal anastamosis (IRA). The nonsteroidal anti-inflammatory drug (NSAID) sulindac and selective cyclooxygenase-2 (COX-2) inhibitor celecoxib reduce polyposis of the retained rectum after colectomy with IRA. Reports of cardiovascular risks of some NSAIDs and selective COX-2 inhibitors have led to promising studies of lower doses in combination with ursodeoxycholic acid, statin, and difluoromethylornithine. Curcumin and eicosapentaenoic acid show efficacy in small clinical trials of FAP chemoprevention. This article will review the concept of chemoprevention and the current clinical literature in FAP chemoprevention.
Topics: Adenomatous Polyposis Coli; Animals; Anticarcinogenic Agents; Chemoprevention; Colectomy; Colorectal Neoplasms; Disease Progression; Genetic Predisposition to Disease; Humans; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 22122775
DOI: 10.1016/j.bpg.2011.08.002