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The Journal of Experimental Medicine May 2017Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription...
Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos-expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.
Topics: Animals; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cholesterol; Diethylnitrosamine; Disease Models, Animal; Drosophila Proteins; Liver; Liver Neoplasms; Mice; Proto-Oncogene Proteins c-fos; Repressor Proteins
PubMed: 28356389
DOI: 10.1084/jem.20160935 -
Current Treatment Options in... Mar 2021To critically examine recently published research in the area of chemoprevention in hereditary polyposis and gastrointestinal cancers, and to briefly review several...
PURPOSE OF REVIEW
To critically examine recently published research in the area of chemoprevention in hereditary polyposis and gastrointestinal cancers, and to briefly review several ongoing chemoprevention trials testing novel agents in this population.
RECENT FINDINGS
Four recent chemoprevention trials in patients with familial adenomatous polyposis (FAP) were identified and reviewed. In the FAPEST trial, the combination of erlotinib+sulindac (compared to placebo) met its primary outcome of decreased duodenal polyp burden. A secondary analysis of lower gastrointestinal tract outcomes also demonstrated significant benefits. Two randomized trials in FAP patients examining combination regimens (celecoxib+DFMO and sulindac+DFMO) failed to meet their primary endpoints. Benefits of further research into these combinations was suggested by efficacy signals seen in secondary and post-hoc analyses. Finally, a randomized trial found curcumin (vs placebo) to have no benefit in reducing colorectal polyp count or size in patients with FAP.
SUMMARY
Progress in developing new and more effective preventive options for patients with hereditary gastrointestinal syndromes continues to be made through the efforts of investigators conducting chemoprevention research.
PubMed: 34211259
DOI: 10.1007/s11938-020-00306-x -
PloS One 2022The purpose of this study was to investigate the effect of incorporating chitosan (Ch) and chitosan oligosaccharides (ChO) into the commercially premixed...
BACKGROUND AND PURPOSE
The purpose of this study was to investigate the effect of incorporating chitosan (Ch) and chitosan oligosaccharides (ChO) into the commercially premixed antibiotic-loaded bone cement (ALBC). We compare antibiotic release profiles, antibacterial activity, and mechanical properties among different ALBC formulations. The hypothesis was that increasing the amount of Ch and ChO in the cement mixture would increase the antibiotics released and bacterial control. ALBC mixed with Ch or ChO may create a greater effect due to its superior dissolving property.
MATERIALS AND METHODS
The bone cement samples used in this project were made from Copal® G+V composed of vancomycin and gentamicin. To prepare the Ch and the ChO mixed bone cement samples, different amounts of Ch and ChO were added to the polymethylmethacrylate matrix with three concentrations (1%, 5%, and 10%). Drug elution assay, antimicrobial assay, in vitro cytotoxicity, and mechanical properties were conducted.
RESULTS
Bone cement samples made from Copal® G+V alone or combined with Ch or ChO can release vancomycin and gentamicin into the phosphate-buffered saline. Mixing ChO into the bone cements can increase the amount of drug released more than Ch. ChO 10% gave the highest amount of antibiotics released. All samples showed good antibacterial properties with good biocompatibility in vitro. The microhardness values of the Ch and ChO groups increased significantly compared to the control group. In all groups tested, the microhardness of bone cements was reduced after the drug eluted out. However, this reduction of the Ch and ChO groups was in line with the control.
INTERPRETATION
Various attempts have been made to improve the ALBC efficacy. In our study, the best bone cement formulation was bone cement mixed with ChO (10%), which had the highest drug release profiles, was biocompatible, and contained antibacterial properties with acceptable mechanical properties. This phenomenon could result from the superior water solubility of the ChO. When ChO leaves the bone cement specimens, it generates pores that could act as a path that exposes the bone cement matrix to the surrounding medium, increasing antibiotic elution. From all above, ChO is a promising substance that could be added to ALBC in order to increase the drug elution rate. However, more in vitro and in vivo experiments are needed before being used in the clinic.
Topics: Bone Cements; Chitosan; Anti-Bacterial Agents; Vancomycin; Sulindac; Gentamicins; Glass Ionomer Cements; Dental Materials; Oligosaccharides
PubMed: 36449553
DOI: 10.1371/journal.pone.0276604 -
BMC Cancer Dec 2015Specificity protein (Sp) transcription factors play pivotal roles in maintaining the phenotypes of many cancers. We hypothesized that the antineoplastic effects of...
BACKGROUND
Specificity protein (Sp) transcription factors play pivotal roles in maintaining the phenotypes of many cancers. We hypothesized that the antineoplastic effects of sulindac and its metabolites were due, in part, to targeting downregulation of Sp transcription factors.
METHODS
The functional effects of sulindac, sulindac sulfone and sulindac sulfide on colon cancer cell proliferation were determined by cell counting. Effects of these compounds on expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes were determined by western blot analysis of whole cell lysates and in transient transfection assays using GC-rich constructs.
RESULTS
Sulindac and its metabolites inhibited RKO and SW480 colon cancer cell growth and the order of growth inhibitory potency was sulindac sulfide>>sulindac sulfone>sulindac. Treatment of SW480 and RKO cells with sulindac sulfide downregulated expression of Sp1, Sp3 and Sp4 proteins. Sulindac sulfide also decreased expression of several Sp-regulated genes that are critical for cancer cell survival, proliferation and angiogenesis and these include survivin, bcl-2, epidermal growth factor receptor (EGFR), cyclin D1, p65 subunit of NFκB and vascular endothelial growth factor (VEGF). Sulindac sulfide also induced reactive oxygen species (ROS) and decreased the level of microRNA-27a in colon cancer cells, which resulted in the upregulation of the Sp-repressor ZBTB10 and this resulted in downregulation of Sp proteins.
CONCLUSIONS
The results suggest that the cancer chemotherapeutic effects of sulindac in colon cancer cells are due, in part, to its metabolite sulindac sulfide which downregulates Sp transcription factors and Sp-regulated pro-oncogenic gene products.
Topics: Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Down-Regulation; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Real-Time Polymerase Chain Reaction; Sp Transcription Factors; Sulindac
PubMed: 26673922
DOI: 10.1186/s12885-015-1956-8 -
BioMed Research International 2017Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of...
Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 ) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 ) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium (' = 0.977, = 0.944). The mean values of , AUC, and AUC of sulindac were significantly higher in FMO3 group than those of FMO3 group ( < 0.05), while the pharmacokinetic parameters except of sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Gene Frequency; Genotype; Healthy Volunteers; Humans; Inflammation; Linkage Disequilibrium; Male; Oxygenases; Polymorphism, Restriction Fragment Length; Sulindac
PubMed: 28331852
DOI: 10.1155/2017/4189678 -
Pharmaceutics Oct 2021The effectiveness of oral drug administration is related to the solubility of a drug in the gastrointestinal tract and its ability to penetrate the biological membranes....
The effectiveness of oral drug administration is related to the solubility of a drug in the gastrointestinal tract and its ability to penetrate the biological membranes. As most new drugs are poorly soluble in water, there is a need to develop novel drug carriers that improve the dissolution rate and increase bioavailability. The aim of this study was to analyze the modification of sulindac release profiles in various pH levels with two APTES ((3-aminopropyl)triethoxysilane)-modified SBA-15 (Santa Barbara Amorphous-15) silicas differing in 3-aminopropyl group content. Furthermore, we investigated the cytotoxicity of the analyzed molecules. The materials were characterized by differential scanning calorimetry, powder X-ray diffraction, scanning and transmission electron microscopy, proton nuclear magnetic resonance and Fourier transformed infrared spectroscopy. Sulindac loaded on the SBA-15 was released in the hydrochloric acidic medium (pH 1.2) and phosphate buffers (pH 5.8, 6.8, and 7.4). The cytotoxicity studies were performed on Caco-2 cell line. The APTES-modified SBA-15 with a lower adsorption capacity towards sulindac released the drug in a less favorable manner. However, both analyzed materials improved the dissolution rate in acidic pH, as compared to crystalline sulindac. Moreover, the SBA-15, both before and after drug adsorption, exhibited insignificant cytotoxicity towards Caco-2 cells. The presented study evidenced that SBA-15 could serve as a non-toxic drug delivery system that enhances the dissolution rate of sulindac and improves its bioavailability.
PubMed: 34683986
DOI: 10.3390/pharmaceutics13101693 -
Pharmacological Research Jan 2019RAS has long been viewed as undruggable due to its lack of deep pockets for binding of small molecule inhibitors. However, recent successes in the development of direct... (Review)
Review
RAS has long been viewed as undruggable due to its lack of deep pockets for binding of small molecule inhibitors. However, recent successes in the development of direct RAS inhibitors suggest that the goal of pharmacological inhibition of RAS in patients may soon be realized. This review will discuss the role of RAS in cancer, the approaches used to develop direct RAS inhibitors, and highlight recent successes in the development of novel RAS inhibitory compounds that target different aspects of RAS biochemistry. In particular, this review will discuss the different properties of RAS that have been targeted by various inhibitors including membrane localization, the different activation states of RAS, effector binding, and nucleotide exchange. In addition, this review will highlight the recent success with mutation-specific inhibitors that exploit the unique biochemistry of the RAS(G12C) mutant. Although this mutation in KRAS accounts for 11% of all KRAS mutations in cancer, it is the most prominent KRAS mutant in lung cancer suggesting that G12C-specific inhibitors may provide a new approach for treating the subset of lung cancer patients harboring this mutant allele. Finally, this review will discuss the involvement of dimerization in RAS function and highlight new approaches to inhibit RAS by specifically interfering with RAS:RAS interaction.
Topics: Animals; Antineoplastic Agents; Cell Membrane; Humans; Neoplasms; Protein Multimerization; ras Proteins
PubMed: 30366101
DOI: 10.1016/j.phrs.2018.10.021 -
Journal of Cellular and Molecular... May 2015Pulmonary fibrosis (PF) is a disease with an unknown cause and a poor prognosis. In this study, we aimed to explore the pathogenesis of PF and the mechanism of sulindac...
Pulmonary fibrosis (PF) is a disease with an unknown cause and a poor prognosis. In this study, we aimed to explore the pathogenesis of PF and the mechanism of sulindac in attenuating bleomycin (BLM)-induced PF. The rat PF model was induced by BLM and verified through histological studies and hydroxyproline assay. The severity of BLM-induced PF in rats and other effects, such as the extent of the wet lung to bw ratios, thickening of alveolar interval or collagen deposition, was obviously ameliorated in sulindac-treated rat lungs compared with BLM-induced lungs. Sulindac also reversed the epithelial mesenchymal transition (EMT) and inhibited the PF process by restoring the levels of E-cadherin and α-smooth muscle actin (SMA) in A549 cells. Our results further demonstrated that the above effects of sulindac might be related to regulating of interferon gamma (IFN-γ) expression, which further affects signal transducers and activators of transcription 3 (STAT3) and phosphorylated STAT3 (p-STAT3) levels. Moreover, higher miR-21 levels with the decreased E-cadherin and increased α-SMA expressions were found in transforming growth factor-β1-treated A549 cells, which can be reversed by sulindac. Collectively, our results demonstrate that by decreasing IFN-γ-induced STAT3/p-STAT3 expression to down-regulate miR-21, sulindac could significantly reverse EMT in A549 cells and prevent BLM-induced PF.
Topics: Actins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bleomycin; Blotting, Western; Cadherins; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Female; Gene Expression; Humans; Interferon-gamma; Lung; MicroRNAs; Microscopy, Fluorescence; Pulmonary Fibrosis; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Signal Transduction; Sulindac
PubMed: 25704671
DOI: 10.1111/jcmm.12506 -
Bosnian Journal of Basic Medical... Apr 2022Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood-onset inflammatory disease characterized by arthritis accompanied by systemic auto-inflammation and...
Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood-onset inflammatory disease characterized by arthritis accompanied by systemic auto-inflammation and extra-articular symptoms. While recent advances have unraveled a range of risk factors, the pathomechanisms involved in SJIA and potential prognostic markers for treatment success remain partly unknown. In this study, we included 70 active SJIA and 55 healthy control patients from the National Center for Biotechnology Information to analyze for differentially expressed genes (DEGs) using R. Functional enrichment analysis, protein-protein interaction (PPI), and gene module construction were performed for DEGs and hub gene set. We additionally examined immune system cell composition with CIBERSORT and predicted prognostic markers and potential treatment drugs for SJIA. In total, 94 upregulated and 24 downregulated DEGs were identified. Two specific modules of interest and eight hub genes (ARG1, DEFA4, HP, MMP8, MMP9, MPO, OLFM4, PGLYRP1) were screened out. Functional enrichment analysis suggested that complex neutrophil-related functions play a decisive role in the disease pathogenesis. CIBERSORT indicated neutrophils, M0 macrophages, CD8+ T cells, and naïve B cells to be relevant drivers of disease progression. Additionally, we identified TPM2 and GZMB as potential prognostic markers for treatment response to canakinumab. Moreover, sulindac sulfide, (-)-catechin, and phenanthridinone were identified as promising treatment agents. This study provides a new insight into molecular and cellular pathogenesis of active SJIA and highlights potential targets for further research.
Topics: Arthritis, Juvenile; Child; Computational Biology; Humans; Neutrophils; Prognosis
PubMed: 34480465
DOI: 10.17305/bjbms.2021.6016 -
The Open Medicinal Chemistry Journal 2018Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon...
BACKGROUND
Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activity and demonstrating xenograft activity.
OBJECTIVE
Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities.
METHOD
A series of sulindac amine analogs were designed and synthesized and then further modified in a "libraries from libraries" approach to produce amide, sulfonamide and N,N-disubstituted sulindac amine sub-libraries. All analogs were screened against three cancer cell lines (prostate, colon and breast).
RESULTS
Several active compounds were identified cancer cell line screening with the most potent compound () in the nanomolar range.
CONCLUSION
Compound and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds.
PubMed: 29492166
DOI: 10.2174/1874104501812010001