COX-2 Inhibitors for Cancer Treatment in Dogs

Cancer is one of the main causes of death in canines and felines, and this fact is probably related to the increase in the longevity of these species. The longer the animals live, the higher the exposure to carcinogenic agents will be. With the high incidence of cancer in companion animals, new studies are currently being performed with the aim of finding therapeutic options which make the complete inhibition of the development of neoplasms in animals possible in the future. The correlation of cyclooxygenase-2 (COX-2) whith the development of cancer opens the way for the use of new therapeutic approaches. This relationship has been suggested based on various studies which established an association between the chronic use of nonsteroidal anti-inflammatory drugs (NSAID) and a decrease in the incidence of colon carcinoma. As cancer progresses, COX-2 participates in the arachidonic acid metabolism by synthesizing prostaglandins which can mediate various mechanisms related to cancer development such as: increase in angiogenesis, inhibition of apoptosis, suppression of the immune response, acquisition of greater invasion capacity and metastasis. Accordingly, overexpression of this enzyme in tumors has been associated with the most aggressive, poor-prognosis cancer types, especially carcinomas. Therefore, treatments which use COX-2 inhibitors such as coxibs, whether administered as single agents or in combination with conventional antineoplastic chemotherapy, are an alternative for extending the survival of our cancer patients.

Identification of continuous interaction sites in PLA(2)-based protein complexes by peptide arrays

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Molecular cloning and biochemical characterization of a myotoxin inhibitor from Bothrops alternatus snake plasma

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Avaliação da expressão da cicloxigenase-2 de macrófagos em diferentes graus histológicos de mastocitoma canino

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Relação da ciclooxigenase-2 com VEGF e a caspase-3 nas neoplasias mamárias de cadelas

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Efeito do celecoxib sobre o desenvolvimento de doença periodontal induzida em ratos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Correlação da ciclooxigenase-2 com Ki-67, P53 e Caspase-3 nas neoplasias de mama de cadela

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Isolation and biochemical characterization of a gamma-type phospholipase A2 inhibitor from Crotalus durissus collilineatus snake serum

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Healing Actions of Essential Oils from Citrus aurantium and d-Limonene in the Gastric Mucosa: The Roles of VEGF, PCNA, and COX-2 in Cell Proliferation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Expressão da ciclooxigenase – 2 (COX-2) em carcinomas mamários espontâneos em cadelas

The immunohistochemistry regarding the expression of cyclooxygenase-2 (COX-2) for the woman’s breast cancer became a routine application due to the biological relevance. It is possible that COX-2 is closely related to tumor angiogenesis, inhibition of apoptosis mechanism, adhesion and metastasis. Herewith the COX-2 expression contributes to verify the malignant potential of the breast cancer. However it is slightly used in female dog’s spontaneous breast carcinomas. Keeping this in mind, the \cox-2 inhibitions appear as a promising perspective for the prevention and treatment of some sorts of cancer. The present dissertation had as main purpose to show the occurrence of the COX-2 expression in some of the female dog’s spontaneous breast carcinomas

Quantificação imunofenotípica de células T reguladoras em cães acometidos por linfoma multicêntrico submetidos ao protocolo quimioterápico chop associado ou não a um firocoxib

Pós-graduação em Medicina Veterinária - FCAV

The adipokine chemerin augments vascular reactivity to contractile stimuli via activation of the MEK-ERK1/2 pathway

Aims: Cytokines interfere with signaling pathways and mediators of vascular contraction. Endothelin-1 (ET-1) plays a major role on vascular dysfunction in conditions characterized by increased circulating levels of adipokines. In the present study we tested the hypothesis that the adipokine chemerin increases vascular contractile responses via activation of ET-1/ET-1 receptors-mediated pathways. Main methods: Male, 10-12 week-old Wistar rats were used. Endothelium-intact and endothelium-denuded aortic rings were incubated with chemerin (0.5 ng/mL or 5 ng/mL, for 1 or 24 h), and isometric contraction was recorded. Protein expression was determined by Western blotting. Key findings: Constrictor responses to phenylephrine (PE) and ET-1 were increased in vessels treated for 1 h with chemerin. Chemerin incubation for 24 h decreased PE contractile response whereas it increased the sensitivity to ET-1. Endothelium removal significantly potentiated chemerin effects on vascular contractile responses to PE and ET-1. Incubation with either an ERK1/2 inhibitor (PD98059) or ETA antagonist (BQ123) abolished chemerin effects on PE- and ET-1-induced vasoconstriction. Phosphorylation of MEK1/2 and ERK1/2 was significantly increased in vessels treated with chemerin for 1 and 24 h. Phosphorylation of these proteins was further increased in vessels incubated with ET-1 plus chemerin. ET-1 increased MEK1/2, ERK1/2 and MKP1 protein expression to values observed in vessels treated with chemerin. Significance: Chemerin increases contractile responses to PE and ET-1 via ERK1/2 activation. Our study contributes to a better understanding of the mechanisms by which the adipose tissue affects vascular function and, consequently, the vascular alterations present in obesity and related diseases. (c) 2012 Elsevier Inc. All rights reserved.

Synthesis, anti-inflammatory activity and molecular docking studies of 2,5-diarylfuran amino acid derivatives

A series of 2,5-diaryl substituted furans functionalized with several amino acids were synthesized and evaluated as the cyclooxygenases COX-1 and COX-2 enzymes inhibitors. The proline-substituted compound inhibited PGE(2) secretion by LPS-stimulated neutrophils, suggesting selectivity for COX-2. Molecular docking studies in the binding site of COX-2 were performed. (C) 2011 Elsevier Masson SAS. All rights reserved.

Characterization of suramin binding sites on the human group IIA secreted phospholipase A(2) by site-directed mutagenesis and molecular dynamics simulation

Suramin is a polysulphonated naphthylurea with inhibitory activity against the human secreted group IIA phospholipase A(2) (hsPLA2GIIA), and we have investigated suramin binding to recombinant hsPLA2GIIA using site-directed mutagenesis and molecular dynamics (MD) simulations. The changes in suramin binding affinity of 13 cationic residue mutants of the hsPLA2GIIA was strongly correlated with alterations in the inhibition of membrane damaging activity of the protein. Suramin binding to hsPLA2GIIA was also studied by MD simulations, which demonstrated that altered intermolecular potential energy of the suramin/mutant complexes was a reliable indicator of affinity change. Although residues in the C-terminal region play a major role in the stabilization of the hsPLA2GIIA/suramin complex, attractive and repulsive hydrophobic and electrostatic interactions with residues throughout the protein together with the adoption of a bent suramin conformation, all contribute to the stability of the complex. Analysis of the h5PLA2GIIA/suramin interactions allows the prediction of the properties of suramin analogues with improved binding and higher affinities which may be candidates for novel phospholipase A(2) inhibitors. (C) 2012 Elsevier Inc. All rights reserved.

Role of an indole-thiazolidine molecule PPAR pan-agonist and COX inhibitor on inflammation and microcirculatory damage in acute gastric lesions

The present study aimed to show the in vivo mechanisms of action of an indole-thiazolidine molecule peroxisome-proliferator activated receptor pan-agonist (PPAR pan) and cyclooxygenase (COX) inhibitor, LYSO-7, in an ethanol/HCl-induced (Et/HCl) gastric lesion model. Swiss male mice were treated with vehicle, LYSO-7 or Bezafibrate (p.o.) 1 hour before oral administration of Et/HCl (60%/0.03M). In another set of assays, animals were injected i.p. with an anti-granulocyte antibody, GW9962 or L-NG-nitroarginine methyl ester (L-NAME) before treatment. One hour after Et/HCl administration, neutrophils were quantified in the blood and bone marrow and the gastric microcirculatory network was studied in situ. The gastric tissue was used to quantify the percentage of damaged area, as well as myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) protein and PPARγ protein and gene expression. Acid secretion was evaluated by the pylorus ligation model. LYSO-7 or Bezafibrate treatment reduced the necrotic area. LYSO-7 treatment enhanced PPARγ gene and protein expression in the stomach, and impaired local neutrophil influx and stasis of the microcirculatory network caused by Et/HCl administration. The effect seemed to be due to PPARγ agonist activity, as the LYSO-7 effect was abolished in GW9962 pre-treated mice. The reversal of microcirculatory stasis, but not neutrophil influx, was mediated by nitric oxide (NO), as L-NAME pre-treatment abolished the LYSO-7-mediated reestablishment of microcirculatory blood flow. This effect may depend on enhanced eNOS protein expression in injured gastric tissue. The pH and concentration of H(+) in the stomach were not modified by LYSO-7 treatment. In addition, LYSO-7 may induce less toxicity, as 28 days of oral treatment did not induce weight loss, as detected in pioglitazone treated mice. Thus, we show that LYSO-7 may be an effective treatment for gastric lesions by controlling neutrophil influx and microcirculatory blood flow mediated by NO