Eicosanoids in platelets and the effect of their modulation by aspirin in the cardiovascular system (and beyond)

Crescente, Marilena; Menke, Laura; Chan, Melissa; Armstrong, Paul C; Warner, Timothy D.

doi:10.1111/bph.14196

Cited by 59 publications

(54 citation statements)

References 143 publications

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“…Concluding, ASA administration to cancer-bearing mice induced some pro-inflammatory changes in the profile of eicosanoids compatible with some reports on COX inhibitors [30,42,[46][47][48], but in contrast with the general view of ASA as an anti-inflammatory agent inhibiting TXA 2 , 11-HETE and 15-HETE production [49,50] and stimulating the generation of antiinflammatory proresolvines (AT-SPMs), such as resolvins (AT-RvDs) and lipoxins (AT-LXs) [50]. Given our findings and those of others, aspirin seems to induce a more complex pattern of changes in the eicosanoid profile in mice as previously thought [50], and, therefore, the effects of low-dose ASA in vivo need to be extensively re-evaluated, in particular in inflammatory conditions.…”

Section: Plos Onesupporting

confidence: 85%

Unexpected effects of long-term treatment with acetylsalicylic acid on late phase of pulmonary metastasis in murine model of orthotopic breast cancer

et al. 2020

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Long-term administration of acetylsalicylic acid (ASA) was effective in prevention of colorectal cancer, whereas the efficacy of this compound in other cancer types, including breast cancer, has been less convincingly documented. Indeed, the antimetastatic effect of lowdose ASA was observed only in the early intravascular phase of metastasis of breast cancer. In the present work, we characterized the effects of long-term treatment with ASA on the late phase of pulmonary metastasis in a mouse orthotopic 4T1 breast cancer model. Mice were treated with ASA at a dose of 12 mg�kg-1 of body weight daily starting one week prior to inoculation of 4T1 breast cancer cells, and the treatment was continued throughout progression of the disease. ASA administration decreased platelet TXB 2 production in ex vivo assays but did not change thrombin-induced platelet reactivity. Although the number of metastases in the lungs remained unchanged in ASA-treated mice, infiltration of inflammatory cells was increased concomitantly with higher G-CSF and serotonin concentrations in the lungs. Pulmonary NO production was compromised compared to control 4T1 mice. ASA treatment also evoked an increase in platelet and granulocyte counts and decreased systemic NO bioavailability along with increased markers of systemic oxidant stress such as higher GSSG/lower GSH concentrations in RBC. Analysis of eicosanoids in stirred blood demonstrated that administration of ASA at a dose of 12 mg�kg-1 to cancer-bearing mice had an effect beyond inhibition of platelet COX-1, suggesting long-term treatment with lowdose aspirin is not a selective murine platelet COX-1/TXA 2 pathway inhibitor in cancer-bearing mice. In summary, quite surprisingly, long-term treatment with low-dose ASA administered until the advanced phase of breast cancer in a murine orthotopic model of 4T1 breast cancer negatively affected the phenotype of the disease.

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Section: Plos Onesupporting

confidence: 85%

Unexpected effects of long-term treatment with acetylsalicylic acid on late phase of pulmonary metastasis in murine model of orthotopic breast cancer

et al. 2020

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“…Aspirin is a special case in the NSAID family of drugs since it prevents rather than precipitates cardiovascular events. The mechanisms by which aspirin protects the cardiovascular system have been reviewed elsewhere (Crescente et al ., ) but involve the unique pharmacology of aspirin as an irreversible inhibitor of COX which allows this NSAID to selectively target TXA 2 release from the anucleate platelet. Thus, all NSAIDs, except aspirin, increase personal risk of a cardiovascular event by as much as 30% (McGettigan and Henry, ; Trelle et al, ; Coxib et al, ; Bally et al, ).…”

Section: Role Of Cox‐2 In Cardiovascular Protection and The Cardiovasmentioning

confidence: 99%

Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system

Mitchell¹,

Kirkby²

2018

British J Pharmacology

179

123

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Eicosanoids represent a diverse family of lipid mediators with fundamental roles in physiology and disease. Within the eicosanoid superfamily are prostanoids, which are specifically derived from arachidonic acid by the enzyme cyclooxygenase (COX). COX has two isoforms; COX-1 and COX-2. COX-2 is the therapeutic target for the nonsteroidal anti-inflammatory drug (NSAID) class of pain medications. Of the prostanoids, prostacyclin, first discovered by Sir John Vane in 1976, remains amongst the best studied and retains an impressive pedigree as one of the fundamental cardiovascular protective pathways. Since this time, we have learnt much about how eicosanoids, COX enzymes and prostacyclin function in the cardiovascular system, knowledge that has allowed us, for example, to harness the power of prostacyclin as therapy to treat pulmonary arterial hypertension and peripheral vascular disease. However, there remain many unanswered questions in our basic understanding of the pathways, and how they can be used to improve human health. Perhaps, the most important and controversial outstanding question in the field remains; 'how do NSAIDs produce their much publicized cardiovascular side-effects?' This review summarizes the history, biology and cardiovascular function of key eicosanoids with particular focus on prostacyclin and other COX products and discusses how our knowledge of these pathways can applied in future drug discovery and be used to explain the cardiovascular side-effects of NSAIDs.

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“…Platelets are also important producers of eicosanoids, lipids derived from polyunsaturated fatty acids (PUFAs), through the catalytic action of cyclooxygenase (COX) and lipoxygenase (LOX). Eicosanoids are crucially involved in several pathophysiological conditions [139], and the intersection between changes in certain platelet-derived eicosanoids and cancer appears particularly intriguing. For example, a multi-omics analysis of serum from metastatic melanoma patients revealed a rise in the concentration of 12-hydroxyeicosatraenoic acid (HETE) and 15-HETE eicosanoids, which are respectively produced by platelet 12-LOX and COX-1 [99].…”

Section: Platelet-derived Bioactive Compoundsmentioning

confidence: 99%

“…For example, a multi-omics analysis of serum from metastatic melanoma patients revealed a rise in the concentration of 12-hydroxyeicosatraenoic acid (HETE) and 15-HETE eicosanoids, which are respectively produced by platelet 12-LOX and COX-1 [99]. These two platelet-derived eicosanoids have also been shown to exert pro-malignant effects in several cancer types, by activating mitogen and angiogenic pathways [139][140][141][142]. Coherently, blockage of COX-1 by aspirin causes the loss of platelet ability to transform human colon carcinoma cells into mesenchymal-like cells [139,143] and the long-term use of low-dose aspirin is associated with a reduction in risk of various cancers [144].…”

Section: Platelet-derived Bioactive Compoundsmentioning

confidence: 99%

The “Janus Face” of Platelets in Cancer

Catani

Savini

Tullio

et al. 2020

IJMS

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Besides their vital role in hemostasis and thrombosis, platelets are also recognized to be involved in cancer, where they play an unexpected central role: They actively influence cancer cell behavior, but, on the other hand, platelet physiology and phenotype are impacted by tumor cells. The existence of this platelet-cancer loop is supported by a large number of experimental and human studies reporting an association between alterations in platelet number and functions and cancer, often in a way dependent on patient, cancer type and treatment. Herein, we shall report on an update on platelet-cancer relationships, with a particular emphasis on how platelets might exert either a protective or a deleterious action in all steps of cancer progression. To this end, we will describe the impact of (i) platelet count, (ii) bioactive molecules secreted upon platelet activation, and (iii) microvesicle-derived miRNAs on cancer behavior. Potential explanations of conflicting results are also reported: Both intrinsic (heterogeneity in platelet-derived bioactive molecules with either inhibitory or stimulatory properties; features of cancer cell types, such as aggressiveness and/or tumour stage) and extrinsic (heterogeneous characteristics of cancer patients, study design and sample preparation) factors, together with other confounding elements, contribute to “the Janus face” of platelets in cancer. Given the difficulty to establish the univocal role of platelets in a tumor, a better understanding of their exact contribution is warranted, in order to identify an efficient therapeutic strategy for cancer management, as well as for better prevention, screening and risk assessment protocols.

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Eicosanoids in platelets and the effect of their modulation by aspirin in the cardiovascular system (and beyond)

Cited by 59 publications

References 143 publications

Unexpected effects of long-term treatment with acetylsalicylic acid on late phase of pulmonary metastasis in murine model of orthotopic breast cancer

Unexpected effects of long-term treatment with acetylsalicylic acid on late phase of pulmonary metastasis in murine model of orthotopic breast cancer

Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system

The “Janus Face” of Platelets in Cancer

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