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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 -
Nature Communications Apr 2023Zika virus (ZIKV) is a potential threat to male reproductive health but the mechanisms underlying its influence on testes during ZIKV infection remain obscure. To...
Zika virus (ZIKV) is a potential threat to male reproductive health but the mechanisms underlying its influence on testes during ZIKV infection remain obscure. To address this question, we perform single-cell RNA sequencing using testes from ZIKV-infected mice. The results reveal the fragility of spermatogenic cells, especially spermatogonia, to ZIKV infection and show that the genes of the complement system are significantly upregulated mainly in infiltrated S100A4 + monocytes/macrophages. Complement activation and its contribution to testicular damage are validated by ELISA, RT‒qPCR and IFA and further verify in ZIKV-infected northern pigtailed macaques by RNA genome sequencing and IFA, suggesting that this might be the common response to ZIKV infection in primates. On this basis, we test the complement inhibitor C1INH and S100A4 inhibitors sulindac and niclosamide for their effects on testis protection. C1INH alleviates the pathological change in the testis but deteriorates ZIKV infection in general. In contrast, niclosamide effectively reduces S100A4 + monocyte/macrophage infiltration, inhibits complement activation, alleviates testicular damage, and rescues the fertility of male mice from ZIKV infection. This discovery therefore encourages male reproductive health protection during the next ZIKV epidemic.
Topics: Male; Mice; Animals; Zika Virus; Zika Virus Infection; Niclosamide; Complement Activation; Sequence Analysis, RNA
PubMed: 37120617
DOI: 10.1038/s41467-023-38223-z -
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 -
Frontiers in Pharmacology 2020Cancer, the second cause of death worldwide, is characterized by several common criteria, known as the "cancer hallmarks" such as unrestrained cell proliferation, cell... (Review)
Review
Cancer, the second cause of death worldwide, is characterized by several common criteria, known as the "cancer hallmarks" such as unrestrained cell proliferation, cell death resistance, angiogenesis, invasion and metastasis. Calcium permeable channels are proteins present in external and internal biological membranes, diffusing Ca ions down their electrochemical gradient. Numerous physiological functions are mediated by calcium channels, ranging from intracellular calcium homeostasis to sensory transduction. Consequently, calcium channels play important roles in human physiology and it is not a surprise the increasing number of evidences connecting calcium channels disorders with tumor cells growth, survival and migration. Multiple studies suggest that calcium signals are augmented in various cancer cell types, contributing to cancer hallmarks. This review focuses in the role of calcium permeable channels signaling in cancer with special attention to the mechanisms behind the remodeling of the calcium signals. Transient Receptor Potential (TRP) channels and Store Operated Channels (SOC) are the main extracellular Ca source in the plasma membrane of non-excitable cells, while inositol trisphosphate receptors (IPR) are the main channels releasing Ca from the endoplasmic reticulum (ER). Alterations in the function and/or expression of these calcium channels, as wells as, the calcium buffering by mitochondria affect intracellular calcium homeostasis and signaling, contributing to the transformation of normal cells into their tumor counterparts. Several compounds reported to counteract several cancer hallmarks also modulate the activity and/or the expression of these channels including non-steroidal anti-inflammatory drugs (NSAIDs) like sulindac and aspirin, and inhibitors of polyamine biosynthesis, like difluoromethylornithine (DFMO). The possible role of the calcium permeable channels targeted by these compounds in cancer and their action mechanism will be discussed also in the review.
PubMed: 32733237
DOI: 10.3389/fphar.2020.00968 -
Cancers Feb 2021Since colorectal cancer is one of the world's most common cancers, studies on its prevention and early diagnosis are an emerging area of clinical oncology these days.... (Review)
Review
Since colorectal cancer is one of the world's most common cancers, studies on its prevention and early diagnosis are an emerging area of clinical oncology these days. For this study, a review of randomized controlled, double-blind clinical trials of selected NSAIDs (aspirin, sulindac and celecoxib) in chemoprevention of colorectal cancer was conducted. The main molecular anticancer activity of NSAIDs is thought to be a suppression of prostaglandin E synthesis via cyclooxygenase-2 inhibition, which causes a decrease in tumor cell proliferation, angiogenesis, and increases apoptosis. The lower incidence of colorectal cancer in the NSAID patients suggests the long-lasting chemopreventive effect of drugs studied. This new approach to therapy of colorectal cancer may transform the disease from a terminal to a chronic one that can be taken under control.
PubMed: 33546238
DOI: 10.3390/cancers13040594 -
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 -
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