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1.
Pharmacol Res ; 185: 106506, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36241001

RESUMO

Clinical and experimental evidence sustain the role of cyclooxygenase (COX)-1 in intestinal tumorigenesis. However, the cell type expressing the enzyme involved and molecular mechanism(s) have not been clarified yet. We aimed to elucidate the role of platelet COX-1 (the target of low-dose aspirin in humans) in intestinal tumorigenesis of ApcMin/+ mice, considered a clinically relevant model. To realize this objective, we generated an ApcMin/+ mouse with a specific deletion of Ptgs1(COX-1 gene name) in megakaryocytes/platelets (ApcMin/+;pPtgs1-/-mice) characterized by profound inhibition of thromboxane(TX)A2 biosynthesis ex vivo (serum TXB2; by 99%) and in vivo [urinary 2,3-dinor-TXB2(TXM), by 79%]. ApcMin/+ mice with the deletion of platelet COX-1 showed a significantly reduced number (67%) and size (32%) of tumors in the small intestine. The intestinal adenomas of these mice had decreased proliferative index associated with reduced COX-2 expression and systemic prostaglandin(PG)E2 biosynthesis (urinary PGEM) vs. ApcMin/+mice. Extravasated platelets were detected in the intestine of ApcMin/+mice. Thus, we explored their contribution to COX-2 induction in fibroblasts, considered the primary polyp cell type expressing the protein. In the coculture of human platelets and myofibroblasts, platelet-derived TXA2 was involved in the induction of COX-2-dependent PGE2 in myofibroblasts since it was prevented by the selective inhibition of platelet COX-1 by aspirin or by a specific antagonist of TXA2 receptors. In conclusion, our results support the platelet hypothesis of intestinal tumorigenesis and provide experimental evidence that selective inhibition of platelet COX-1 can mitigate early events of intestinal tumorigenesis by restraining COX-2 induction.


Assuntos
Polipose Intestinal , Megacariócitos , Camundongos , Humanos , Animais , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Transformação Celular Neoplásica , Carcinogênese , Aspirina/farmacologia
2.
Pharmacol Res ; 170: 105744, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34182131

RESUMO

Enhanced platelet activation has been reported in patients with essential hypertension and heart failure. The possible contribution of platelet-derived thromboxane (TX)A2 in their pathophysiology remains unclear. We investigated the systemic TXA2 biosynthesis in vivo and gene expression of its receptor TP in 22 essential hypertension patients and a mouse model of salt-sensitive hypertension. The contribution of platelet TXA2 biosynthesis on enhanced blood pressure (BP) and overload-induced cardiac fibrosis was explored in mice by treating with low-dose Aspirin, resulting in selective inhibition of platelet cyclooxygenase (COX)-1-dependent TXA2 generation. In essential hypertensive patients, systemic biosynthesis of TXA2 [assessed by measuring its urinary metabolites (TXM) reflecting predominant platelet source] was enhanced together with higher gene expression of circulating leukocyte TP and TGF-ß, vs. normotensive controls. Similarly, in hypertensive mice with prostacyclin (PGI2) receptor (IP) deletion (IPKO) fed with a high-salt diet, enhanced urinary TXM, and left ventricular TP overexpression were detected vs. normotensive wildtype (WT) mice. Increased cardiac collagen deposition and profibrotic gene expression (including TGF-ß) was found. Low-dose Aspirin administration caused a selective inhibition of platelet TXA2 biosynthesis and mitigated enhanced blood pressure, cardiac fibrosis, and left ventricular profibrotic gene expression in IPKO but not WT mice. Moreover, the number of myofibroblasts and extravasated platelets in the heart was reduced. In cocultures of human platelets and myofibroblasts, platelet TXA2 induced profibrotic gene expression, including TGF-ß1. In conclusion, our results support tailoring low-dose Aspirin treatment in hypertensive patients with unconstrained TXA2/TP pathway to reduce blood pressure and prevent early cardiac fibrosis.


Assuntos
Antifibróticos/farmacologia , Anti-Hipertensivos/farmacologia , Aspirina/farmacologia , Plaquetas/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cardiomiopatias/prevenção & controle , Hipertensão Essencial/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Tromboxano A2/sangue , Adulto , Animais , Biomarcadores/sangue , Plaquetas/metabolismo , Cardiomiopatias/sangue , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Hipertensão Essencial/sangue , Hipertensão Essencial/complicações , Hipertensão Essencial/fisiopatologia , Feminino , Fibrose , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Receptores de Epoprostenol/genética , Receptores de Epoprostenol/metabolismo , Receptores de Tromboxanos/metabolismo
3.
J Pharmacol Exp Ther ; 370(3): 416-426, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31248980

RESUMO

Inflammatory bowel disease (IBD) is associated with an increased risk for thromboembolism, platelet activation, and abnormalities in platelet number and size. In colitis, platelets can extravasate into the colonic interstitium. We generated a mouse with a specific deletion of cyclooxygenase (COX)-1 in megakaryocytes/platelets [(COX-1 conditional knockout (cKO)] to clarify the role of platelet activation in the development of inflammation and fibrosis in dextran sodium sulfate (DSS)-induced colitis. The disease activity index was assessed, and colonic specimens were evaluated for histologic features of epithelial barrier damage, inflammation, and fibrosis. Cocultures of platelets and myofibroblasts were performed. We found that the specific deletion of COX-1 in platelets, which recapitulated the human pharmacodynamics of low-dose aspirin, that is, suppression of platelet thromboxane (TX)A2 production associated with substantial sparing of the systemic production of prostacyclin, resulted in milder symptoms of colitis, in the acute phase, and almost complete recovery from the disease after DSS withdrawal. Reduced colonic accumulation of macrophages and myofibroblasts and collagen deposition was found. Platelet-derived TXA2 enhanced the ability of myofibroblasts to proliferate and migrate in vitro, and these effects were prevented by platelet COX-1 inhibition or antagonism of the TXA2 receptor. Our findings allow a significant advance in the knowledge of the role of platelet-derived TXA2 in the development of colitis and fibrosis in response to intestinal damage and provide the rationale to investigate the potential efficacy of the antiplatelet agent low-dose aspirin in limiting the inflammatory response and fibrosis associated with IBD. SIGNIFICANCE STATEMENT: Inflammatory bowel disease (IBD) is characterized by the development of a chronic inflammatory response, which can lead to intestinal fibrosis for which currently there is no medical treatment. Through the generation of a mouse with specific deletion of cyclooxygenase-1 in megakaryocytes/platelets, which recapitulates the human pharmacodynamics of low-dose aspirin, we demonstrate the important role of platelet-derived thromboxane A2 in the development of experimental colitis and fibrosis, thus providing the rationale to investigate the potential efficacy of low-dose aspirin in limiting the inflammation and tissue damage associated with IBD.


Assuntos
Plaquetas/metabolismo , Colite/induzido quimicamente , Colite/enzimologia , Ciclo-Oxigenase 1/deficiência , Ciclo-Oxigenase 1/genética , Sulfato de Dextrana/farmacologia , Deleção de Genes , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Colite/sangue , Colite/genética , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Humanos , Megacariócitos/efeitos dos fármacos , Megacariócitos/metabolismo , Camundongos , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/patologia , Prostaglandinas/biossíntese
4.
Cell Mol Life Sci ; 74(19): 3491-3507, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28488110

RESUMO

Platelets are anucleated cells that circulate in the blood as sentinels of tissue integrity. In fact, they are rich in a plethora of proteins and other factors stored in different granules which they selectively release upon stimulation. Moreover, platelets synthesize a vast number of lipids and release various types of vesicles, including exosomes which are rich in genetic material. Platelets possess a central function to interact with other cell types, including inflammatory cells and cancer cells. Recent findings have enlightened the capacity of platelets to induce changes in the phenotype of cancer cells which acquire invasiveness thus enhancing their metastatic potential. Thus, it has been hypothesized that targeting the platelet may represent a novel strategy to prevent the development and progression of cancer. This is supported by the efficacy of the antiplatelet agent low-dose aspirin. Studies are ongoing to verify whether other antiplatelet agents share the anticancer effectiveness of aspirin.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Metástase Neoplásica/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Animais , Aspirina/farmacologia , Aspirina/uso terapêutico , Plaquetas/metabolismo , Eicosanoides/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Lisofosfolipídeos/metabolismo , Terapia de Alvo Molecular/métodos , Metástase Neoplásica/patologia , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Glicoproteínas da Membrana de Plaquetas/metabolismo , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Receptores de Prostaglandina E Subtipo EP3/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP3/metabolismo
5.
Biochem Soc Trans ; 43(4): 707-14, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26551717

RESUMO

Platelets are activated by the interaction with cancer cells and release enhanced levels of lipid mediators [such as thromboxane (TX)A2 and prostaglandin (PG)E2, generated from arachidonic acid (AA) by the activity of cyclooxygenase (COX)-1], granule content, including ADP and growth factors, chemokines, proteases and Wnt proteins. Moreover, activated platelets shed different vesicles, such as microparticles (MPs) and exosomes (rich in genetic material such as mRNAs and miRNAs). These platelet-derived products induce several phenotypic changes in cancer cells which confer high metastatic capacity. A central event involves an aberrant expression of COX-2 which influences cell-cycle progression and contribute to the acquisition of a cell migratory phenotype through the induction of epithelial mesenchymal transition genes and down-regulation of E-cadherin expression. The identification of novel molecular determinants involved in the cross-talk between platelets and cancer cells has led to identify novel targets for anti-cancer drug development.


Assuntos
Plaquetas/citologia , Ciclo-Oxigenase 2/metabolismo , Neoplasias/patologia , Ativação Plaquetária , Plaquetas/metabolismo , Comunicação Celular , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica , Neoplasias/metabolismo
6.
Biochem Pharmacol ; 178: 114094, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32535107

RESUMO

The most recognized mechanism of aspirin (acetylsalicylic acid, ASA) action, at therapeutic dosing, is the inhibition of prostanoid biosynthesis through the acetylation of cyclooxygenase (COX)-isozymes (COX-1 at serine-529 and COX-2 at serine-516). Whether aspirin, also when given at the low-doses recommended for cardiovascular prevention, reduces the risk of colorectal cancer by affecting COX-2 activity in colorectal adenomatous lesions is still debated. We aimed to develop a direct biomarker of aspirin action on COX-2 by assessing the extent of acetylation of COX-2 at serine-516 using the AQUA strategy, enabling absolute protein quantitation by liquid chromatography-mass spectrometry. We compared the extent of acetylation and the inhibition of prostanoid biosynthesis by ASA using human recombinant COX-2 (hu-COX-2), the human colon cancer cell line HCA-7, isolated human monocytes stimulated with LPS (lipopolysaccharide) or human intestinal epithelial cells stimulated with interleukin (IL)-1ß. Hu-COX-2 exposed in vitro to an excess of ASA was acetylated by approximately 40-50% associated with the inhibition of COX-2 activity by 80-90%. In the three cell-types expressing COX-2, the extent of COX-2 acetylation and reduction of prostaglandin (PG) E2 biosynthesis by ASA was concentration-dependent with comparable EC50 values (in the low µM range). The maximal % acetylation of COX-2 averaged 80%, at ASA 1000 µM, and was associated with a virtually complete reduction of PGE2 biosynthesis (97%). In conclusion, we have developed a proteomic assay to evaluate the extent of acetylation of COX-2 at serine-516 by aspirin; its use in clinical studies will allow clarifying the mechanism of action of aspirin as anticancer agent.


Assuntos
Aspirina/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/antagonistas & inibidores , Células Epiteliais/efeitos dos fármacos , Processamento de Proteína Pós-Traducional , Acetilação , Sequência de Aminoácidos , Ácido Araquidônico/metabolismo , Linhagem Celular Tumoral , Cromatografia Líquida , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Dinoprostona/biossíntese , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Expressão Gênica , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Interleucina-1beta/farmacologia , Lipopolissacarídeos/farmacologia , Espectrometria de Massas , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Serina/metabolismo
7.
Vascul Pharmacol ; 89: 1-11, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28089842

RESUMO

The prevention of cancer development and its progression is an urgent unmet medical need. Novel knowledge on the biology of cancer has evidenced that genetic changes occurring within cancer cells contribute, but are not sufficient, for tumor promotion and progression. The results of clinical studies and experimental animal models have suggested pursuing new avenues for the prevention of cancer development in the early stages, by using drugs that modulate platelet responses and those interfering with the synthesis and action of the mediators of inflammation. In fact, malignant tumors often develop at sites of chronic injury associated with platelet activation and chronic inflammation. In this review, we cover the evidence supporting this hypothesis and the rationale for the pharmacological treatment with antiplatelet agents, including low-dose aspirin, and antiinflammatory drugs to curb tumorigenesis and malignant progression. The evidence for a chemopreventive effect of low-dose aspirin against colorectal cancer (CRC) has been recently found appropriate by the U.S. Preventive Services Task Force, which recommends the use of the drug for primary prevention of cardiovascular disease and CRC.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticarcinógenos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/prevenção & controle , Inflamação/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Cicatrização/efeitos dos fármacos , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Humanos , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Microambiente Tumoral
8.
Oncotarget ; 7(22): 32462-77, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27074574

RESUMO

We investigated whether platelets prime colon cancer cells for metastasis and whether pharmacological inhibition of platelet function may prevent it. Coculturing HT29 human colon carcinoma cells with human platelets led to the induction of mesenchymal-like cancer cells characterized by downregulation of E-cadherin and upregulation of Twist1, enhanced cell mobility and a proaggregatory action on platelets. These changes were prevented by different antiplatelet agents, aspirin[an inhibitor of cyclooxygenase(COX)-1], DG-041[an antagonist of prostaglandin(PG)E2 EP3 receptor] and ticagrelor (a P2Y12 receptor antagonist). The injection of HT29 cells, exposed to platelets in vitro, into the tail vein of humanized immunodeficient mice led to higher incidence of lung metastasis compared to the injection of untreated HT29 cells. This effect was associated with enhanced systemic biosynthesis of thromboxane(TX)A2 and PGE2in vivo. Platelet COX-1 inhibition by aspirin administration to mice prevented the increased rate of metastasis as well as the enhanced production of TXA2 and PGE2 induced by the in vitro priming of HT29 cells by platelets. In conclusion, targeting platelet COX-1 with low-dose aspirin exerts an antimetastatic action by averting the stem cell mimicry of cancer cells associated with enhanced proaggregatory effects induced by platelet-tumor cell interactions. These effects may be shared by other antiplatelet drugs.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Plaquetas/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Animais , Plaquetas/patologia , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Dinoprostona/farmacologia , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células HT29 , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica , Células Tumorais Cultivadas
9.
Curr Pharm Des ; 21(35): 5116-26, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26369679

RESUMO

The results of clinical studies have shown that the chronic administration of aspirin, even at the lowdoses (75-100 mg daily) recommended for the prevention of cardiovascular disease, is associated with a reduction of cancer incidence and mortality, in particular colorectal cancer (CRC). The mechanism of action of aspirin as an antineoplastic agent remains controversial. However, data of clinical pharmacology and several features of the chemopreventive effect of aspirin, emerged from clinical trials, suggest that the antiplatelet effect of aspirin plays a central role in its anticancer effects. In addition to their contribution to tumor metastasis, platelets may play a role in the early phases of tumorigenesis. In response to lifestyle and environment factors, intestinal epithelial damage/ dysfunction may be associated with platelet activation, initially as a mechanism to repair the damage. However, if the platelet response is unconstrained, it may contribute to the development of chronic inflammation. Altogether these events lead to alter the normal functions of intestinal epithelial cells and may translate into cellular transformation through several mechanisms, including the overexpression of cyclooxygenase(COX)-2 and epidermal growth factor receptor (EGFR), which are considered early events in colorectal tumorigenesis. Thus, antiplatelet agents may play a role in the prevention of CRC by modifying epigenetic events involved in early phases of colorectal tumorigenesis. Finally, we carried out a critical review of the literature on off-target mechanisms of aspirin action as anticancer drug.


Assuntos
Anticarcinógenos/farmacologia , Aspirina/farmacologia , Neoplasias Colorretais/prevenção & controle , Animais , Anticarcinógenos/administração & dosagem , Aspirina/administração & dosagem , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Epigênese Genética , Humanos , Inflamação/patologia , Inflamação/prevenção & controle , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacologia
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