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Scientific Reports Jul 2022This study aimed to explore the mechanisms of action of a sulindac acetohydrazide derivative, N'-(4-dimethylaminobenzylidene)-2-1-(4-(methylsulfinyl)...
This study aimed to explore the mechanisms of action of a sulindac acetohydrazide derivative, N'-(4-dimethylaminobenzylidene)-2-1-(4-(methylsulfinyl) benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl) acetohydrazide, against anticancer drug cisplatin induced organ damage. Using a rodent model, various markers of organ function and signaling pathways were examined and validated by molecular docking studies. The study involves five groups of animals: control, DMSO, CDDP, CDDP + DMFM, and DMFM. Biochemical enzyme activity, histopathology, tissue antioxidant, and oxidative stress markers were examined. RT-PCR and western blot analyses were conducted for the expression of inducible cyclooxygenase enzyme (COX-2), nuclear factor kappa beta (NF-κB), p65, IL-1, TNF-α, and inducible nitric oxide synthase (iNOS). Flow cytometry analysis of CD4 + TNF-α, CD4 + COX-2, and CD4 + STAT-3 cells in whole blood was performed. Structural and dynamic behavior of DMFM upon binding with receptor molecule molecular docking and dynamic simulations were performed using bioinformatics tools and software. Treatment with DMFM reversed cisplatin-induced malondialdehyde (MDA) and nitric oxide (NO) induction, whereas the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD) in the kidney, heart, liver, and brain tissues were increased. DMFM administration normalized plasma levels of biochemical enzymes. We observed a marked decline in CD4 + STAT3, TNF-α, and COX2 cell populations in whole blood after treatment with DMFM. DMFM downregulated the expression factors related to inflammation at the mRNA and protein levels, i.e., IL-1, TNF-α, iNOS, NF-κB, STAT-3, and COX-2. Dynamic simulations and in silico docking data supports the experimental findings. Our experimental and in silico results illustrated that DMFM may affect protective action against cisplatin-induced brain, heart, liver, and kidney damage via reduction of inflammation and ROS.
Topics: Antioxidants; Cisplatin; Cyclooxygenase 2; Humans; Hydrazines; Inflammation; Interleukin-1; Molecular Docking Simulation; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Signal Transduction; Sulindac; Tumor Necrosis Factor-alpha
PubMed: 35817806
DOI: 10.1038/s41598-022-15950-9 -
Yakugaku Zasshi : Journal of the... 2018In recent years, pharmaceuticals and personal care products (PPCPs) have emerged as significant pollutants of aquatic environments and have been detected at levels in... (Review)
Review
In recent years, pharmaceuticals and personal care products (PPCPs) have emerged as significant pollutants of aquatic environments and have been detected at levels in the range of ng/L to μg/L. The source of PPCPs is humans and livestock that have been administered pharmaceuticals and subsequently excreted them via urine and feces. Unlike agricultural chemicals, the environmental dynamics of PPCPs is not examined and they would undergo structural transformation by environmental factors, e.g., sunlight, microorganisms and treatments in sewage treatment plants (STPs). Processing at STPs can remove various PPCPs; however, they are not removed completely and some persist in the effluents. In this study, we examined the degradation of 9 pharmaceuticals (acetaminophen, amiodarone, dapsone, dexamethasone, indomethacin, raloxifene, phenytoin, naproxen, and sulindac) by sunlight or UV, and investigated the ecotoxicological variation of degradation products. Sunlight (UVA and UVB) degraded most pharmaceuticals, except acetaminophen and phenytoin. Similar results were obtained with UVB and UVA. All the pharmaceuticals were photodegraded by UVC, which is used for sterilization in STPs. Ecotoxicity assay using the luminescent bacteria test (ISO11348) indicated that UVC irradiation increased the toxicity of acetaminophen and phenytoin significantly. The photodegraded product of acetaminophen was identified as 1-(2-amino-5-hydroxyphenyl)ethanone and that of phenytoin as benzophenone, and the authentic compounds showed high toxicity. Photodegraded products of PPCPs are a concern in ecotoxicology.
Topics: Acetaminophen; Animals; Benzophenones; Cosmetics; Ecotoxicology; Humans; Pharmaceutical Preparations; Photolysis; Sunlight; Ultraviolet Rays; Water Pollutants, Chemical; Water Pollution, Chemical
PubMed: 29503416
DOI: 10.1248/yakushi.17-00177-2 -
Molecular Cancer Therapeutics Jul 2021Immune-checkpoint inhibitor (ICI) therapy has been widely used to treat different human cancers, particularly advanced solid tumors. However, clinical studies have...
Immune-checkpoint inhibitor (ICI) therapy has been widely used to treat different human cancers, particularly advanced solid tumors. However, clinical studies have reported that ICI immunotherapy benefits only ∼15% of patients with colorectal cancer, specifically those with tumors characterized by microsatellite instability (MSI), a molecular marker of defective DNA mismatch repair (dMMR). For the majority of patients with colorectal cancer who carry proficient MMR (pMMR), ICIs have shown little clinical benefit. In this study, we examined the efficacy of sulindac to enhance the response of pMMR colorectal cancer to anti-PD-L1 immunotherapy. We utilized a CT26 syngeneic mouse tumor model to compare the inhibitory effects of PD-L1 antibody (Ab), sulindac, and their combination on pMMR colorectal cancer tumor growth. We found that mice treated with combination therapy showed a significant reduction in tumor volume, along with increased infiltration of CD8 T lymphocytes in the tumor tissues. We also demonstrated that sulindac could downregulate PD-L1 by blocking NF-κB signaling, which in turn led to a decrease in exosomal PD-L1. Notably, PD-L1 Ab can be bound and consumed by exosomal PD-L1 in the blood circulation. Therefore, in combination therapy, sulindac downregulating PD-L1 leads to increased availability of PD-L1 Ab, which potentially improves the overall efficacy of anti-PD-L1 therapy. We also show that low-dose sulindac does not appear to have a systemic inhibitory effect on prostaglandin E2 (PGE2). In conclusion, our findings provide unique insights into the mechanism of action and efficacy for sulindac as an immunomodulatory agent in combination with anti-PD-L1 therapy for the treatment of pMMR colorectal cancer.
Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Immunological; B7-H1 Antigen; Cell Line, Tumor; Colorectal Neoplasms; DNA Mismatch Repair; Disease Models, Animal; Humans; Immune Checkpoint Inhibitors; Lymphocytes, Tumor-Infiltrating; Mice; NF-kappa B; Signal Transduction; Sulindac; Tumor Burden
PubMed: 33879557
DOI: 10.1158/1535-7163.MCT-20-0934 -
Cancer Prevention Research... Jan 2018To identify gene expression biomarkers and pathways targeted by sulindac and erlotinib given in a chemoprevention trial with a significant decrease in duodenal polyp... (Randomized Controlled Trial)
Randomized Controlled Trial
To identify gene expression biomarkers and pathways targeted by sulindac and erlotinib given in a chemoprevention trial with a significant decrease in duodenal polyp burden at 6 months ( < 0.001) in familial adenomatous polyposis (FAP) patients, we biopsied normal and polyp duodenal tissues from patients on drug versus placebo and analyzed the RNA expression. RNA sequencing was performed on biopsies from the duodenum of FAP patients obtained at baseline and 6-month endpoint endoscopy. Ten FAP patients on placebo and 10 on sulindac and erlotinib were selected for analysis. Purity of biopsied polyp tissue was calculated from RNA expression data. RNAs differentially expressed between endpoint polyp and paired baseline normal were determined for each group and mapped to biological pathways. Key genes in candidate pathways were further validated by quantitative RT-PCR. RNA expression analyses of endpoint polyp compared with paired baseline normal for patients on placebo and drug show that pathways activated in polyp growth and proliferation are blocked by this drug combination. Directly comparing polyp gene expression between patients on drug and placebo also identified innate immune response genes (IL12 and IFNγ) preferentially expressed in patients on drug. Gene expression analyses from tissue obtained at endpoint of the trial demonstrated inhibition of the cancer pathways COX2/PGE2, EGFR, and WNT. These findings provide molecular evidence that the drug combination of sulindac and erlotinib reached the intended tissue and was on target for the predicted pathways. Furthermore, activation of innate immune pathways from patients on drug may have contributed to polyp regression. .
Topics: Adenomatous Polyposis Coli; Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cyclooxygenase 1; Duodenal Neoplasms; ErbB Receptors; Erlotinib Hydrochloride; Female; Follow-Up Studies; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Prognosis; RNA, Messenger; Sulindac; Young Adult
PubMed: 29109117
DOI: 10.1158/1940-6207.CAPR-17-0130 -
Drug Discovery Today Aug 2020Although numerous reports conclude that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer activity, this common drug class is not recommended for long-term... (Review)
Review
Although numerous reports conclude that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer activity, this common drug class is not recommended for long-term use because of potentially fatal toxicities from cyclooxygenase (COX) inhibition. Studies suggest the mechanism responsible for the anticancer activity of the NSAID sulindac is unrelated to COX inhibition but instead involves an off-target, phosphodiesterase (PDE). Thus, it might be feasible develop safer and more efficacious drugs for cancer indications by targeting PDE5 and PDE10, which are overexpressed in various tumors and essential for cancer cell growth. In this review, we describe the rationale for using the sulindac scaffold to design-out COX inhibitory activity, while improving potency and selectivity to inhibit PDE5 and PDE10 that activate cGMP/PKG signaling to suppress Wnt/β-catenin transcription, cancer cell growth, and tumor immunity.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Humans; Neoplasms; Phosphodiesterase Inhibitors; Signal Transduction; Sulindac; Transcription, Genetic; Wnt Proteins; beta Catenin
PubMed: 32562844
DOI: 10.1016/j.drudis.2020.06.008 -
Pharmaceutics Dec 2022As acetylcholinesterase (AChE) plays a crucial role in advancing Alzheimer's disease (AD), its inhibition is a promising approach for treating AD. Sulindac is an NSAID...
As acetylcholinesterase (AChE) plays a crucial role in advancing Alzheimer's disease (AD), its inhibition is a promising approach for treating AD. Sulindac is an NSAID of the aryl alkanoic acid class, consisting of a indene moiety, which showed neuroprotective behavior in recent studies. In this study, newer Indene analogs were synthesized and evaluated for their in vitro AChE inhibition. Additionally, compared with donepezil as the standard drug, these Indene analogs were accessed for their cell line-based toxicity study on SH-SY5Y cell line. The molecule , having hydrogen bond donor (HBD) at para-position, showed maximum AChE inhibition potential (IC 13.86 ± 0.163 µM) in the indene series. Further, the showed maximum BuChE inhibition potential (IC = 48.55 ± 0.136 µM) with a selectivity ratio of 3.50 and reasonable antioxidant properties compared to ascorbic acid (using DPPH assay). (at a dose level: of 10 µM, 20 µM) effectively inhibited AChE-induced Aβ aggregation and showed no significant toxicity up to 30 mM against SH-SY5Y cell lines.
PubMed: 36678724
DOI: 10.3390/pharmaceutics15010094 -
Oncology Letters May 2018The present study aimed to observe the effects of sulindac sulfide on the proliferation and apoptosis of human breast cancer cells MCF-7, and to explore the potential...
The present study aimed to observe the effects of sulindac sulfide on the proliferation and apoptosis of human breast cancer cells MCF-7, and to explore the potential underlying molecular mechanism. The inhibitory ratio was detected using a cell counting kit-8 assay. The changes in cell cycle distribution were assessed using flow cytometry (FCM). Furthermore, the changes in cell apoptosis rates were detected by Hoechst 33258 staining and FCM coupled with Annexin V-FITC/propidium iodide (PI) staining. In addition, the protein expression was detected using western blotting. Sulindac sulfide was able to inhibit the proliferation of breast cancer in a dose- and time-dependent manner. In addition, sulindac sulfide altered the cell cycle of breast cancer cells. The results of Hoechst 33258 staining and FCM coupled with Annexin V-FITC/PI staining demonstrated that sulindac sulfide could significantly induce the apoptosis of MCF-7 cells in a dose-dependent, and time-dependent manner. The western blot analysis demonstrated the protein expression of Bcl-2 was downregulated, and Bax and cleaved caspase-3 were upregulated. The results of the present study suggest that sulindac sulfide can inhibit the proliferation and induce the apoptosis of MCF-7 cells.
PubMed: 29849803
DOI: 10.3892/ol.2018.8331 -
Molecules (Basel, Switzerland) Dec 2015Copal is the Spanish word used to describe aromatic resins from several genera of plants. Mexican copal derives from several Bursera spp., Protium copal, some Pinus spp.... (Review)
Review
Copal is the Spanish word used to describe aromatic resins from several genera of plants. Mexican copal derives from several Bursera spp., Protium copal, some Pinus spp. (e.g., P. pseudostrobus) and a few Fabaceae spp. It has been used for centuries as incense for religious ceremonies, as a food preservative, and as a treatment for several illnesses. The aim of this review is to analyze the chemical composition and biological activity of commercial Mexican Bursera copal.
Topics: Bursera; Fabaceae; Food Preservatives; Humans; Mexico; Resins, Plant; Sulindac
PubMed: 26703535
DOI: 10.3390/molecules201219849 -
Cells Feb 2020Application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is limited by the challenges in their efficient differentiation. Recently, the Wingless...
Application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is limited by the challenges in their efficient differentiation. Recently, the Wingless (Wnt) signaling pathway has emerged as the key regulator of cardiomyogenesis. In this study, we evaluated the effects of cyclooxygenase inhibitors on cardiac differentiation of hPSCs. Cardiac differentiation was performed by adherent monolayer based method using 4 hPSC lines (HES3, H9, IMR90, and ES4SKIN). The efficiency of cardiac differentiation was evaluated by flow cytometry and RT-qPCR. Generated hPSC-CMs were characterised using immunocytochemistry, electrophysiology, electron microscopy, and calcium transient measurements. Our data show that the COX inhibitors Sulindac and Diclofenac in combination with CHIR99021 (GSK-3 inhibitor) efficiently induce cardiac differentiation of hPSCs. In addition, inhibition of COX using siRNAs targeted towards COX-1 and/or COX-2 showed that inhibition of COX-2 alone or COX-1 and COX-2 in combination induce cardiomyogenesis in hPSCs within 12 days. Using IMR90-Wnt reporter line, we showed that inhibition of COX-2 led to downregulation of Wnt signalling activity in hPSCs. In conclusion, this study demonstrates that COX inhibition efficiently induced cardiogenesis via modulation of COX and Wnt pathway and the generated cardiomyocytes express cardiac-specific structural markers as well as exhibit typical calcium transients and action potentials. These cardiomyocytes also responded to cardiotoxicants and can be relevant as an in vitro cardiotoxicity screening model.
Topics: Cardiotoxicity; Cell Differentiation; Cyclooxygenase Inhibitors; Doxorubicin; Human Embryonic Stem Cells; Humans; Induced Pluripotent Stem Cells; Models, Biological; Myocytes, Cardiac; Organogenesis; Pluripotent Stem Cells; Sulindac
PubMed: 32120775
DOI: 10.3390/cells9030554 -
Toxicology Reports 2016As legacy toxicogenomics databases have become available, improved data mining approaches are now key to extracting and visualizing subtle relationships between...
As legacy toxicogenomics databases have become available, improved data mining approaches are now key to extracting and visualizing subtle relationships between toxicants and gene expression. In the present study, a novel "aggregating bundles of clusters" (ABC) procedure was applied to separate cholestatic from non-cholestatic drugs and model toxicants in the Johnson & Johnson (Janssen) rat liver toxicogenomics database [3]. Drug-induced cholestasis is an important issue, particularly when a new compound enters the market with this liability, with standard preclinical models often mispredicting this toxicity. Three well-characterized cholestasis-responsive genes (Cyp7a1, Mrp3 and Bsep) were chosen from a previous in-house Janssen gene expression signature; these three genes show differing, non-redundant responses across the 90+ paradigm compounds in our database. Using the ABC procedure, extraneous contributions were minimized in comparisons of compound gene responses. All genes were assigned weights proportional to their correlations with Cyp7a1, Mrp3 and Bsep, and a resampling technique was used to derive a stable measure of compound similarity. The compounds that were known to be associated with rat cholestasis generally had small values of this measure relative to each other but also had large values of this measure relative to non-cholestatic compounds. Visualization of the data with the ABC-derived signature showed a very tight, essentially identically behaving cluster of robust human cholestatic drugs and experimental cholestatic toxicants (ethinyl estradiol, LPS, ANIT and methylene dianiline, disulfiram, naltrexone, methapyrilene, phenacetin, alpha-methyl dopa, flutamide, the NSAIDs--indomethacin, flurbiprofen, diclofenac, flufenamic acid, sulindac, and nimesulide, butylated hydroxytoluene, piperonyl butoxide, and bromobenzene), some slightly less active compounds (3'-acetamidofluorene, amsacrine, hydralazine, tannic acid), some drugs that behaved very differently, and were distinct from both non-cholestatic and cholestatic drugs (ketoconazole, dipyridamole, cyproheptadine and aniline), and many postulated human cholestatic drugs that in rat showed no evidence of cholestasis (chlorpromazine, erythromycin, niacin, captopril, dapsone, rifampicin, glibenclamide, simvastatin, furosemide, tamoxifen, and sulfamethoxazole). Most of these latter drugs were noted previously by other groups as showing cholestasis only in humans. The results of this work suggest that the ABC procedure and similar statistical approaches can be instrumental in combining data to compare toxicants across toxicogenomics databases, extract similarities among responses and reduce unexplained data varation.
PubMed: 28959545
DOI: 10.1016/j.toxrep.2016.01.009