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1.
Medicine (Baltimore) ; 99(40): e22544, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019464

RESUMO

BACKGROUND: Clinical studies have shown that celecoxib can significantly inhibit the development of tumors, and basic experiments and in vitro experiments also provide a certain basis, but it is not clear how celecoxib inhibits tumor development in detail. METHODS: A literature search of all major academic databases was conducted (PubMed, China National Knowledge Internet (CNKI), Wan-fang, China Science and Technology Journal Database (VIP), including the main research on the mechanisms of celecoxib on tumors. RESULTS: Celecoxib can intervene in tumor development and reduce the formation of drug resistance through multiple molecular mechanisms. CONCLUSION: Celecoxib mainly regulates the proliferation, migration, and invasion of tumor cells by inhibiting the cyclooxygenases-2/prostaglandin E2 signal axis and thereby inhibiting the phosphorylation of nuclear factor-κ-gene binding, Akt, signal transducer and activator of transcription and the expression of matrix metalloproteinase 2 and matrix metalloproteinase 9. Meanwhile, it was found that celecoxib could promote the apoptosis of tumor cells by enhancing mitochondrial oxidation, activating mitochondrial apoptosis process, promoting endoplasmic reticulum stress process, and autophagy. Celecoxib can also reduce the occurrence of drug resistance by increasing the sensitivity of cancer cells to chemotherapy drugs.


Assuntos
Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Celecoxib/efeitos adversos , Celecoxib/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Dinoprostona/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Adv Exp Med Biol ; 1274: 29-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894506

RESUMO

Prostanoids (prostaglandins, prostacyclin and thromboxane) belong to the oxylipin family of biologically active lipids generated from arachidonic acid (AA). Protanoids control numerous physiological and pathological processes. Cyclooxygenase (COX) is a rate-limiting enzyme involved in the conversion of AA into prostanoids. There are two COX isozymes: the constitutive COX-1 and the inducible COX-2. COX-1 and COX-2 have similar structures, catalytic activities, and subcellular localizations but differ in patterns of expression and biological functions. Non-selective COX-1/2 or traditional, non-steroidal anti-inflammatory drugs (tNSAIDs) target both COX isoforms and are widely used to relieve pain, fever and inflammation. However, the use of NSAIDs is associated with various side effects, particularly in the gastrointestinal tract. NSAIDs selective for COX-2 inhibition (coxibs) were purposefully designed to spare gastrointestinal toxicity, but predisposed patients to increased cardiovascular risks. These health complications from NSAIDs prompted interest in the downstream effectors of the COX enzymes as novel drug targets. This chapter describes various safety issues with tNSAIDs and coxibs, and discusses the current development of novel classes of drugs targeting the prostanoid pathway, including nitrogen oxide- and hydrogen sulfide-releasing NSAIDs, inhibitors of prostanoid synthases, dual inhibitors, and prostanoid receptor agonists and antagonists.


Assuntos
Antagonistas de Prostaglandina/farmacologia , Antagonistas de Prostaglandina/uso terapêutico , Prostaglandinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Humanos , Prostaglandina-Endoperóxido Sintases/metabolismo
3.
Anticancer Res ; 40(9): 5309-5311, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878822

RESUMO

BACKGROUND/AIM: Experimental studies have shown that celecoxib is related to the downregulation of Tregs and an increase in the therapeutic efficacy of PD-1 inhibitors; however, such effect has not been shown in human cancers. Our report confirmed the synergistic effect of celecoxib with a PD-1 inhibitor. CASE REPORT: A 57-year-old male with advanced pulmonary adenocarcinoma was treated with nivolumab monotherapy as 5th line sequential treatment. Although the patient experienced tumor remission, regrowth of the primary tumor was observed and he complained of lumbar pain. Therefore, celecoxib (400 mg/day) was initiated without cessation of nivolumab. Chest radiography revealed a marked shrinkage of the primary site, with a decreasing trend of carcinoma embryonic antigen. CONCLUSION: This is the report of a case of recovery of sensitivity to nivolumab by additional treatment with celecoxib.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Celecoxib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Sinergismo Farmacológico , Receptores ErbB/genética , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Radiografia Torácica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
4.
Cancer Invest ; 38(8-9): 463-475, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32772580

RESUMO

In the present study, we searched selective cytotoxicity and mitochondria mediated apoptosis of novel COX-2 inhibitor 2-(4-(Methylsulfonyl)phenyl)imidazo[1,2-a] pyridine-8-carboxylic acid on B-lymphocytes and their mitochondria isolated from normal subjects and acute lymphoblastic leukemia (ALL) patients' blood. Our results showed this compound can selectively induce cellular and mitochondrial toxicity on ALL B-lymphocytes and mitochondria without any toxic effects on normal B-lymphocytes and their mitochondria. Taken together, the results of this study suggest that cancerous mitochondria are a potential target for the ALL B-lymphocytes. Selective toxicity of COX-2 inhibitor in cancerous mitochondria could be an attractive therapeutic option for the effective clinical management of therapy-resistant ALL.


Assuntos
Linfócitos B/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Mitocôndrias/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos B/patologia , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Citocromos c/metabolismo , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/enzimologia , Membranas Mitocondriais/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Espécies Reativas de Oxigênio/metabolismo , Succinato Desidrogenase/metabolismo
5.
Int J Nanomedicine ; 15: 5345-5360, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801693

RESUMO

Background: Soft corals have been endorsed as a plentiful source of bioactive compounds with promising anti-inflammatory activities; therefore, exploring their potential as source of anti-inflammatory metabolites has stimulated a growing research interest. Purpose: To investigate the anti-inflammatory potential of the soft coral, Nephthea sp., in its bulk and silver nanostructure. Metabolomics analysis of Nephthea sp., followed by molecular docking studies, was also conducted in order to explore and predict the secondary metabolites that might provide its inhibitory actions on inflammation. Materials and Methods: The petroleum ether and ethyl acetate fractions were used to synthesize silver nanoparticles. The prepared silver nanoparticles were characterized through UV-vis spectrophotometric, transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR) analyses. Testing for the anti-inflammatory activity was performed against COX-1 and COX-2. Furthermore, liquid chromatography-mass spectrometry (LC-MS) based metabolomics analysis and molecular docking were also applied. Results: A variety of secondary metabolites were identified, among them, sesquiterpenes were found to prevail. The petroleum ether and acetone fractions of Nephthea sp. showed the highest COX-2 inhibitory activities, possibly attributable to their substantial contents of terpenoids. Additionally, the green synthesized silver nanoparticles of both the petroleum ether and ethyl acetate fractions of Nephthea sp. demonstrated higher anti-COX-2 properties. Conclusion: The obtained results showed the effectiveness of non-targeted metabolomics technique in metabolic profiling of Nephthea sp., helping the search for new bioactive metabolites in future chemical studies on this soft coral. The interesting anti-inflammatory potential of the tested extracts and their nanoparticles could also be relevant to the development of new, effective anti-inflammatory agents.


Assuntos
Antozoários/metabolismo , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Nanopartículas Metálicas/química , Prata/química , Alcanos/química , Animais , Antozoários/química , Anti-Inflamatórios/síntese química , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Química Verde , Humanos , Metabolômica , Simulação de Acoplamento Molecular , Metabolismo Secundário , Sesquiterpenos/análise , Espectrometria de Massas por Ionização por Electrospray , Espectroscopia de Infravermelho com Transformada de Fourier
6.
Drug Discov Ther ; 14(3): 129-134, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32669521

RESUMO

The aim of this randomized, single-blind, active-controlled pilot study was to investigate the clinical efficacy of oral supplementation with Verbascox®, a proprietary herbal extract capable of inhibiting human cyclooxygenase-2 (COX-2), in patients with mild-to-moderate osteoarthritis (OA) of the knee. Patients in the control group (n = 50) did not undergo any treatment (watchful waiting). Patients in the Verbascox® group (n = 50) received oral supplementation (800 mg/day) with the herbal extract for 2 weeks. The final study group consisted of patients (n = 50) who received celecoxib, a known pharmacological inhibitor of COX-2, 200 mg/day for 2 weeks. Examining physicians and laboratory personnel were blinded to group assignment, whereas patients were unblinded. All participants were evaluated using standard measures of pain relief and improvement in functional capacity at baseline, after 1 week, and at the end of the 2-week treatment course. Moreover, serum levels of substance P (SP), a member of the tachykinin family of neuropeptides involved in pain perception, were measured at the three time points. Both Verbascox® and celecoxib reduced pain, improved functional capacity, and lowered serum SP levels at 2 weeks compared with baseline, without significant inter-arm differences. Both Verbascox® and celecoxib showed a limited number of treatment-emergent adverse events. In summary, oral supplementation with Verbascox® (800 mg/day) in patients with mild-to-moderate OA of the knee is as effective and safe as a standard therapeutic dose of celecoxib in terms of pain relief and improvement in functional capacity after a 2-week treatment course.


Assuntos
Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Preparações de Plantas/uso terapêutico , Adulto , Idoso , Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Preparações de Plantas/farmacologia , Método Simples-Cego , Resultado do Tratamento
7.
J Biol Regul Homeost Agents ; 34(3): 785-794, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723437

RESUMO

Previous reports indicated that specific cyclooxygenase-2 (COX-2) inhibitor suppresses osteoarthritis (OA). This study aimed to further explore the possible mechanism of Rofecoxib as a COX-2 inhibitor on the inhibition of chondrocyte (CH) hypertrophic development and tested the optimal treatment of Rofecoxib on CH. Basically, IL-1ß was used as a stimulus to establish a degenerated CH model. Immunofluorescence, Western blot, and RT-PCR were performed to determine the gene expression of Axin2, ß-catenin, GSK3ß, collagen X, collagen II, COX-2, PGE-2, SOX-9, Runx-2, and MMP- 13 expression. Cell Counting Kit (CCK-8) assay was used to analyze the viability of CHs. The data indicated that Rofecoxib significantly inhibited COX-2 expression and had less harmful effects on CH viability. Rofecoxib reversed the IL-1ß-induced upregulation of collagen X, COX-2, PGE-2, Runx-2, and MMP-13 expression, and promoted the viability of collagen II, SOX-9 expression of CHs. Furthermore, Rofecoxib suppressed Axin2, ß-catenin, and GSK3ß expression of the Wnt pathway, which was activated by IL-1ß or human recombinant Wnt-1 protein treatment. Therefore, Rofecoxib is an effective COX-2 inhibitor that protects CHs from hypertrophy by suppression of the Wnt/ß-catenin pathway.


Assuntos
Condrócitos/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Lactonas/farmacologia , Sulfonas/farmacologia , Via de Sinalização Wnt , Células Cultivadas , Condrócitos/citologia , Humanos , Hipertrofia , beta Catenina
9.
Chem Biol Interact ; 326: 109128, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32416088

RESUMO

Exposure to mycotoxins is mostly by ingestion but also occurs by the dermal and inhalation routes. The present study for the first time demonstrated that mycotoxin Deoxynivalenol (DON), permeates through Swiss albino mice skin, which demands awareness of health risks in people who are dermally exposed to mycotoxins especially agricultural farmers. Despite the widespread contamination of DON in food commodities studies to alleviate DON's toxicity are sparsely reported. Thus effective measures to combat mycotoxins associated toxicity remains an imperative aspect to be considered from the angle of dermal exposure. Topical application of Celecoxib (1-2 mg), followed by DON (100 µg) application on the dorsal side of mice, resulted in substantial decrease in DON-induced (i) edema, hyperplasia, cell proliferation (ii) inhibition of cytokine and prostaglandin-E2 levels (iii) phosphorylation of ERK1/2, JNK, p38, MAPKKs, CREB, P90-RSK (iv) downregulation of c-Jun, c- Fos, phospho-NF-kB and their downstream target proteins cyclin D1 and COX-2. Using Ro-31-8220 (Protein-Kinase-C inhibitor), it was observed PKC was responsible for DON induced upregulation of COX-2 and iNOS proteins. Treatment of Celecoxib decreased DON-induced translocation of Protein Kinase C isozymes (α,ε,γ), demonstrating the role of PKC in DON-mediated biochemical and molecular alterations responsible for its dermal toxicity. The present findings indicate that topical application of celecoxib is effective in the management of inflammatory skin disorders induced by foodborne fungal toxin DON. The skin permeation potential of Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor NSAID, was also assessed, and the results indicated that the permeation was relatively lower as compared to the oral mode of administration. Hence topical use of celecoxib may be preferred over oral dosing because of lower systemic absorption and to avoid the unwanted side effects. This study provides a prospect for exploring the clinical efficacy of topically applied COX-2 inhibitors for the management of inflammatory skin disorders induced by foodborne fungal toxins.


Assuntos
Celecoxib/farmacologia , Proliferação de Células/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Proteína Quinase C/metabolismo , Pele/efeitos dos fármacos , Tricotecenos/efeitos adversos , Animais , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Feminino , Inflamação/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Pele/metabolismo , Dermatopatias/tratamento farmacológico , Dermatopatias/metabolismo
10.
Adv Exp Med Biol ; 1195: 137-148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468468

RESUMO

In the present work a series of N'-arylidene-2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazides were synthesized by refluxing the intermediate 2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazide with various substituted benzaldehyde in the presence of glacial acetic acid. The intermediate 2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazide 2 was prepared by stirring 4-((naphthalen-2-yl)methylene)-2-phenyloxazol-5(4H)-one with hydrazine hydrate in the presence of absolute ethanol. The chemical structures of the compounds were established by IR, 1H NMR and mass spectral data. All the compounds were evaluated for anti-inflammatory (in vivo, in vitro) activity and performed docking against COX-2. The compounds 3a, 3c and 3o showed good inhibition of COX-2 in in vitro studies (0.75 µM, 0.5 µM and 0.7 µM as IC50, respectively). The compounds 3c, 3e and 3f were found to be more active than standard drug phenylbutazone at equidose. Molecular docking studies showed that compound 3 m exhibited good binding affinity against COX-2 with docking score 9.328 kcal/mol, when compared to the standard celecoxib.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Hidrazonas/química , Hidrazonas/uso terapêutico , Estrutura Molecular , Relação Estrutura-Atividade
11.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276316

RESUMO

Neuroinflammation is considered to be one of the potential causes for the development of neurodegenerative diseases, including Alzheimer's disease. In this study, we evaluated the effect of four newly synthesized pyrrolo[3,4-d]pyridazinone derivatives on the neuron-like PC12 cells under simulated inflammation conditions by preincubation with lipopolysaccharide (LPS). Our novel derivatives are selective cyclooxygenase-2 (COX-2) inhibitors and have similar effects to nonsteroidal anti-inflammatory drugs (NSAIDs). We assessed viability (LDH assay), metabolic activity (MTT assay), DNA damage (number of double-strand breaks measured by fast halo assay), and the neuronal features of cells (average neurite length and neurite outgrowth measured spectrofluorimetrically). DCF-DA and Griess assays were also performed, which allowed determining the impact of the tested compounds on the level of oxygen free radicals and nitrites. LPS administration significantly negatively affected the results in all tests performed, and treatment with the tested derivatives in most cases significantly reduced this negative impact. Multiple-criteria decision analysis indicated that overall, the best results were observed for compounds 2a and 2b at a concentration of 10 µM. The new derivatives showed intense activity against free oxygen radicals and nitrites. Reduced reactive oxygen species level also correlated with a decrease in the number of DNA damage. The compounds improved neuronal features, such as neurite length and outgrowth, and they also increased cell viability and mitochondrial activity. Our results suggest that derivatives 2a and 2b may also act additionally on mechanisms other than 3a and 3b.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Inflamação/tratamento farmacológico , Neurônios/efeitos dos fármacos , Piridazinas/farmacologia , Doença de Alzheimer , Animais , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Neurônios/patologia , Células PC12 , Piridazinas/uso terapêutico , Ratos
12.
Cancer Res ; 80(12): 2612-2627, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32265226

RESUMO

Current cancer treatments are largely based on the genetic characterization of primary tumors and are ineffective for metastatic disease. Here we report that DNA methyltransferase 3B (DNMT3B) is induced at distant metastatic sites and mediates epigenetic reprogramming of metastatic tumor cells. Multiomics analysis and spontaneous metastatic mouse models revealed that DNMT3B alters multiple pathways including STAT3, NFκB, PI3K/Akt, ß-catenin, and Notch signaling, which are critical for cancer cell survival, apoptosis, proliferation, invasion, and colonization. PGE2 and IL6 were identified as critical inflammatory mediators in DNMT3B induction. DNMT3B expression levels positively correlated with human metastatic progression. Targeting IL6 or COX-2 reduced DNMT3B induction and improved chemo or PD1 therapy. We propose a novel mechanism linking the metastatic microenvironment with epigenetic alterations that occur at distant sites. These results caution against the "Achilles heel" in cancer therapies based on primary tumor characterization and suggests targeting DNMT3B induction as new option for treating metastatic disease. SIGNIFICANCE: These findings reveal that DNMT3B epigenetically regulates multiple pro-oncogenic signaling pathways via the inflammatory microenvironment at distant sites, cautioning the clinical approach basing current therapies on genetic characterization of primary tumors.


Assuntos
Neoplasias da Mama/patologia , DNA (Citosina-5-)-Metiltransferases/metabolismo , Dinoprostona/metabolismo , Interleucina-6/metabolismo , Neoplasias Pulmonares/secundário , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral/transplante , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Progressão da Doença , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Interleucina-6/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Receptor de Morte Celular Programada 1/imunologia , Estudo de Prova de Conceito , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
13.
Acta Biochim Pol ; 67(1): 41-47, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32129972

RESUMO

The chemical composition of Succisa pratensis is not well known. The existing data indicate a substantial content of flavonoids, which include luteolin and apigenin 7-glucosides. The aim of this study was to elaborate the isolation protocol of these flavonoids from flowers and leaves of S. pratensis, to carry out their characterization, as well as evaluate the effect of S. pratensis extracts on activation of transcription factor NF-κB and α-amylase activity. The extraction protocol applied in this study allowed isolation and characterization of flavonoid fraction of S. pratensis. Their identity was confirmed by NMR spectra analysis, UV spectroscopy and electrospray ionization-tandem MS evaluation. Treatment of pancreatic α-amylase with S. pratensis extract inhibited this enzyme's activity to an extent comparable to that of isolated luteolin and apigenin 7-glucosides. Incubation of HepG2 cells for 24 h with S. pratensis extracts or isolated flavonoids resulted in moderate reduction in NF-κB transcription factor activation evaluated in terms of translocation of its active subunits from cytosol into nucleus and subsequently diminished expression of the COX-2 gene. Expression of NF-κB was also reduced. The most significantly diminished NF-κB activation and expression, as well as COX-2 expression, was found to result from treatment with isolated flavonoids and ethyl acetate extract of S. pratensis leaves. These results indicate that S. pratensis flavonoids may modulate the metabolic and signaling pathways whose deregulation is related to pathogenesis of liver cancer. Further studies are required to confirm these observations and assess the chemopreventive and/or therapeutic potential of the S. pratensis herb.


Assuntos
Apigenina/farmacologia , Glucosídeos/farmacologia , Neoplasias Hepáticas/metabolismo , Luteolina/farmacologia , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , alfa-Amilases/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dipsacaceae/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/etiologia , Extratos Vegetais/uso terapêutico , alfa-Amilases/antagonistas & inibidores
14.
Cancer Res ; 80(11): 2257-2272, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32193288

RESUMO

Quiescent cancer cells are believed to cause cancer progression after chemotherapy through unknown mechanisms. We show here that human non-small cell lung cancer (NSCLC) cell line-derived, quiescent-like, slow-cycling cancer cells (SCC) and residual patient-derived xenograft (PDX) tumors after chemotherapy experience activating transcription factor 6 (ATF6)-mediated upregulation of various cytokines, which acts in a paracrine manner to recruit fibroblasts. Cancer-associated fibroblasts (CAF) underwent transcriptional upregulation of COX2 and type I collagen (Col-I), which subsequently triggered a slow-to-active cycling switch in SCC through prostaglandin E2 (PGE2)- and integrin/Src-mediated signaling pathways, leading to cancer progression. Both antagonism of ATF6 and cotargeting of Src/COX2 effectively suppressed cytokine production and slow-to-active cell cycling transition in SCC, withholding cancer progression. Expression of COX2 and Col-I and activation of Src were observed in patients with NSCLC who progressed while receiving chemotherapy. Public data analysis revealed significant association between COL1A1 and SRC expression and NSCLC relapse. Overall, these findings indicate that a proinflammatory niche created by the interplay between SCC and CAF triggers tumor progression. SIGNIFICANCE: Cotargeting COX2 and Src may be an effective strategy to prevent cancer progression after chemotherapy.


Assuntos
Fibroblastos Associados a Câncer/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Citocinas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Fator 6 Ativador da Transcrição/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Celecoxib/administração & dosagem , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Citocinas/biossíntese , Dasatinibe/administração & dosagem , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos SCID , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Quinases da Família src/antagonistas & inibidores
15.
Parasite Immunol ; 42(6): e12713, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32173875

RESUMO

Canine leishmaniasis (CanL) is caused by the intracellular parasite Leishmania infantum. Prostaglandin E2 (PGE2 ) exerts potent regulatory effects on the immune system in experimental model Leishmania infection, but this influence has not yet been studied in CanL. In this study, PGE2 and PGE2 receptor levels and the regulatory effect of PGE2 on arginase activity, NO2 , IL-10, IL-17, IFN-γ, TNF-α and parasite load were evaluated in cultures of splenic leucocytes obtained from dogs with CanL in the presence of agonists and inhibitors. Our results showed that splenic leucocytes from dogs with CanL had lower EP2 receptor levels than those of splenic leucocytes from healthy animals. We observed that NO2 levels decreased when the cells were treated with a PGE2 receptor agonist (EP1/EP2/EP3) or COX-2 inhibitor (NS-398) and that TNF-α, IL-17 and IFN-γ cytokine levels decreased when the cells were treated with a PGE2 receptor agonist (EP2) or PGE2 itself. The parasite load in splenic leucocyte cell cultures from dogs with CanL decreased after stimulation of the cells with PGE2 . We conclude that Leishmania infection of dogs modulates PGE2 receptors and speculate that the binding of PGE2 to its receptors may activate the microbicidal capacity of cells.


Assuntos
Citocinas/imunologia , Dinoprostona/metabolismo , Doenças do Cão/tratamento farmacológico , Leishmania infantum/imunologia , Leishmaniose/veterinária , Receptores de Prostaglandina E/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/agonistas , Dinoprostona/antagonistas & inibidores , Doenças do Cão/imunologia , Doenças do Cão/parasitologia , Cães , Leishmaniose/tratamento farmacológico , Leishmaniose/imunologia , Óxido Nítrico/análise , Nitrobenzenos/farmacologia , Carga Parasitária , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina E/fisiologia , Sulfonamidas/farmacologia , Fator de Necrose Tumoral alfa/imunologia
16.
J Enzyme Inhib Med Chem ; 35(1): 744-758, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32183576

RESUMO

A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold 3-14 and their in vitro antitumor activity was evaluated. Compounds 4a, 4b, 6b, 7b, 13, and 14 had the most potent antitumor activity (IC50 range: 5.13-17.95 µM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives 4a, 4b, 7b, and 13 were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-α. Compounds 4a and 13 potently inhibited TNF-α (IC50 values: 2.01 and 6.72 µM, respectively) compared with celecoxib (IC50=6.44 µM). Compounds 4b and 13 potently inhibited COX-2 (IC50 values: 1.08 and 1.88 µM, respectively) comparable to that of celecoxib (IC50=0.68 µM). Compounds 4a, 7b, and 13 inhibited PDE4B (IC50 values: 5.62, 5.65, and 3.98 µM, respectively) compared with the reference drug roflumilast (IC50=1.55 µM). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied.HighlightsAntitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated.The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-α inhibitors.Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-α inhibition.Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets.


Assuntos
Anisóis/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Simulação de Acoplamento Molecular , Inibidores da Fosfodiesterase 4/farmacologia , Anisóis/síntese química , Anisóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores
17.
BMC Complement Med Ther ; 20(1): 49, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046692

RESUMO

BACKGROUND: Inflammation is one of the key components in the initiation and progression of hepatic diseases. If not treated, inflammation may cause cell dysplasia, and ultimately cancer. In the current study, we investigated the anti-inflammatory and anti-cancer activities of plant isolated compound Lirioresinol B Dimethyl Ether (LBDE) extracted from the seeds of Magnolia fargesii CHENG (Magnoliaceae) against HepG2 cells as well as in BALB/C male mice. METHODS: We assessed the antioxidant and anti-proliferative effects of plant compounds using DPPH assay and HepG2 cell lines. Carbon tetrachloride (CCl4) and Diethylnitrosamine (DEN) were used to induce liver cell dysplasia followed by hepatocellular carcinoma (HCC) in BALB/C male mice for 12 weeks. We investigated the underlying mechanism by using histopathology and immunoblot experiments. RESULTS: Intraperitoneal injection of LBDE (50 mg/kg body weight/day) inhibited CCl4-induced HCC. Free radical scavenging assay shows the strong anti-oxidant activity of LBDE. Western blot results show that LBDE down-regulated nuclear factor kappa B (NFκB) and cyclooxygenase (COX-2) by preventing the phosphorylation of I kappa B alpha (IκBα) in CCl4 treated group. LBDE also improved liver function by decreasing Alkaline Phosphatase (ALP), aspartate aminotransferase (AST) and Alanine Aminotransferase (ALT) levels. Histopathology results revealed that LBDE decreased granulomas and express normal morphology of hepatocytes. CONCLUSIONS: These preliminary results show that LBDE has the potential to inhibit CCl4-induced liver cell dysplasia and prevents cancer development by regulating NFκB/COX-2 activation.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Furanos/farmacologia , Cirrose Hepática/tratamento farmacológico , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/antagonistas & inibidores , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Ciclo-Oxigenase 2 , Modelos Animais de Doenças , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Sementes
18.
Fitoterapia ; 141: 104470, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31917300

RESUMO

Phytochemical investigations on Physalis. alkekengi L. var. franchetii, a widespread traditional Chinese medicine, led to the isolation and identification of three new sesquiterpenoids physalisitins A-C (1-3). Their structures were elucidated by NMR and HRESIMS analysis, and their absolute configurations were determined by quantum chemical NMR and ECD calculations, as well as by comparing their optical rotation values with those known analogues. All of the isolated compounds were evaluated for their cyclooxygenase-2 (COX-2) inhibitory activity. Compounds 1-3 dose-dependently inhibited the COX-2 enzyme with IC50 values of 3.22 ± 0.25, 6.35 ± 0.84, and 11.13 ± 1.47 µM, respectively.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Physalis/química , Sesquiterpenos/farmacologia , Bioensaio , Inibidores de Ciclo-Oxigenase 2/química , Modelos Moleculares , Estrutura Molecular , Plantas Medicinais/química , Sesquiterpenos/química
19.
Arch Pharm (Weinheim) ; 353(3): e1900293, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31917485

RESUMO

A new series of 1,4-diarylazetidin-2-one derivatives (ß-lactams) were designed and synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the 0.05-0.11 µM range, and COX-2 selectivity indexes in the range of 170-703.7. Among the synthesized ß-lactams, 3-methoxy-4-(4-(methylsulfonyl)phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (4j) possessing trimethoxy groups at the N-1 phenyl ring exhibited the highest COX-2 inhibitory selectivity and potency, even more potent than the reference drug celecoxib. The analgesic activity of the synthesized compounds was also determined using the formalin test. Compound 4f displayed the best analgesic activity among the synthesized molecules. Molecular modeling studies indicated that the methylsulfonyl pharmacophore group can be inserted into the secondary pocket of the COX-2 active site for interactions with Arg513 . The structure-activity data acquired indicate that the ß-lactam ring moiety constitutes a suitable scaffold to design new 1,4-diarylazetidin-2-ones with selective COX-2 inhibitory activity.


Assuntos
Analgésicos/farmacologia , Azetidinas/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dor/tratamento farmacológico , beta-Lactamas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Azetidinas/síntese química , Azetidinas/química , Gatos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , beta-Lactamas/síntese química , beta-Lactamas/química
20.
Eur J Med Chem ; 189: 112066, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31982653

RESUMO

The current therapeutic demand focuses more on the discovery of safer NSAIDs rather than exploring more potent alternatives. The dual COX-2/5-LOX inhibition is a promising strategy for designing compounds with an enhanced efficacy, reduced side-effects and a broader anti-inflammatory spectrum in comparison to classical NSAIDs. In the present study, a hybridization strategy was adopted to combine the binding features of the non-selective COX inhibitor "sulindac" and the selective COX-2 inhibitor "celecoxib" which show 5-LOX inhibitory activity with that of licofelone and a celecoxib pyridone analogue which show dual COX-2/5-LOX inhibitory activity to design new series of pyrazole sulfonamide derivatives which, by design, should possess dual COX-2/5-LOX inhibitory activity. All the newly synthesized compounds were initially tested for their potential analgesic activity, then candidates that showed potential analgesic activity, were selected for the subsequent anti-inflammatory activity evaluation, as well as, ulcerogenicity testing. Moreover, in vitro assessment of their COX-1, COX-2 and 5-LOX inhibitory activities were performed. The benzothiophen-2-yl pyrazole carboxylic acid derivative 5b showed the most potent analgesic and anti-inflammatory activities surpassing that of celecoxib and indomethacin. It showed potent COX-1, COX-2 and 5-LOX inhibitory activity with IC50 of 5.40, 0.01 and 1.78 µM, respectively, showing a selectivity index of 344.56 that was much better than the used reference standards and its parent compounds, confirming its selectivity towards COX-2 over COX-1. The prodrug ester derivatives 6c and 6d showed equipotent activity to their parent compound 5b with no gastric ulcerogenicity. Molecular docking simulations confirmed that the newly synthesized compounds possess the structural features required for binding to the target enzymes COX-2 and 5-LOX.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Antiulcerosos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Inibidores de Lipoxigenase/farmacologia , Analgésicos/síntese química , Animais , Anti-Inflamatórios/síntese química , Antiulcerosos/síntese química , Araquidonato 5-Lipoxigenase/química , Ciclo-Oxigenase 1/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Humanos , Inibidores de Lipoxigenase/síntese química , Masculino , Camundongos , Pirazóis/química , Ratos , Ratos Wistar , Úlcera Gástrica/tratamento farmacológico , Sulfonamidas/química
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