Review of vorapaxar for the prevention of atherothrombotic events

Wang, Amy

doi:10.1517/14656566.2015.1099629

Cited by 14 publications

(11 citation statements)

References 30 publications

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“…Although in vitro and in vivo results suggest that the control of PAR1-mediated signaling may represent a promising strategy for the treatment of malignancy, currently only vorapaxar (SCH530348) is approved, as a PAR-1 antagonist, for patients with a history of myocardial infarction or peripheral arterial disease in the United States and with a history of myocardial infarction in Europe [ 109 ]. The clinical development of atopaxar (E5555), another PAR-1 antagonist, is limited to phase 1 and phase 2 trials [ 110 ].…”

Section: Effects Of Antiplatelet Agents In Cancermentioning

confidence: 99%

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Antithrombotic Agents and Cancer

Bruno,

Dovizio,

Tacconelli

et al. 2018

Cancers

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Platelet activation is the first response to tissue damage and, if unrestrained, may promote chronic inflammation-related cancer, mainly through the release of soluble factors and vesicles that are rich in genetic materials and proteins. Platelets also sustain cancer cell invasion and metastasis formation by fostering the development of the epithelial-mesenchymal transition phenotype, cancer cell survival in the bloodstream and arrest/extravasation at the endothelium. Furthermore, platelets contribute to tumor escape from immune elimination. These findings provide the rationale for the use of antithrombotic agents in the prevention of cancer development and the reduction of metastatic spread and mortality. Among them, low-dose aspirin has been extensively evaluated in both preclinical and clinical studies. The lines of evidence have been considered appropriate to recommend the use of low-dose aspirin for primary prevention of cardiovascular disease and colorectal cancer by the USA. Preventive Services Task Force. However, two questions are still open: (i) the efficacy of aspirin as an anticancer agent shared by other antiplatelet agents, such as clopidogrel; (ii) the beneficial effect of aspirin improved at higher doses or by the co-administration of clopidogrel. This review discusses the latest updates regarding the mechanisms by which platelets promote cancer and the efficacy of antiplatelet agents.

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Section: Effects Of Antiplatelet Agents In Cancermentioning

confidence: 99%

“…Despite the strong rationale and these encouraging effects on cancer cells in vitro, the potential use of these drugs in long-term treatments in chemoprevention or chemotherapy seems to be not viable due to their possible side effects, including the significantly increased risk of bleeding [ 109 ].…”

Section: Effects Of Antiplatelet Agents In Cancermentioning

confidence: 99%

Antithrombotic Agents and Cancer

Bruno,

Dovizio,

Tacconelli

et al. 2018

Cancers

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“…Vorapaxar is the first PAR-1 inhibitor approved for clinical use. Regarding to vorapaxar, phase 3 clinical trial data has been available since 2012, and the parent drug company Merck has filed for submission of approval to the US FDA, as well as the European Medicines Agency (EMA) [ 13 – 14 ]. Its main indication is the reduction in thrombotic cardiovascular events in patients with previous myocardial infaction or symptomatic peripheral artery disease.…”

Section: Introductionmentioning

confidence: 99%

Protease-activated receptor-1 (PAR-1): a promising molecular target for cancer

Liu

Song

et al. 2017

Oncotarget

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PAR-1 is expressed not only in epithelium, neurons, astrocytes, immune cells, but also in cancer-associated fibroblasts, ECs (epithelial cells), myocytes of blood vessels, mast cells, and macrophages in tumor microenvironment, whereas PAR-1 stimulates macrophages to synthesize and secrete thrombin as well as other growth factors, resulting in enhanced cell proliferation, tumor growth and metastasis. Therefore, considerable effort has been devoted to the development of inhibitors targeting PAR-1. Here, we provide a comprehensive review of PAR-1’s role in cancer invasiveness and dissemination, as well as potential therapeutic strategies targeting PAR-1 signaling.

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“…Therefore, the current study may represent a cautionary note on the long‐term use of PAR‐1 inhibitors. The clinical use of PAR‐1 inhibitors to prevent thromboembolic complications is relatively recent , making it impossible to know whether long‐term PAR‐1 inhibition has any impact, positive or negative, on tumorigenesis in humans. Several studies have shown a correlation between long‐term anticoagulation and a decreased incidence of multiple types of cancer, including prostate cancer , suggesting that thrombin may play a role in early events that are important in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Protease‐activated receptor‐1 impedes prostate and intestinal tumor progression in mice

Adams

Sharma

Rosenfeldt

et al. 2018

Journal of Thrombosis and Haemostasis

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Essentials Protease activated receptor-1 (PAR-1) has been proposed to drive cancer progression. Surprisingly, PAR-1 deletion accelerated tumor progression in two distinct experimental settings. PAR-1 deletion was shown to limit the apoptosis of transformed epithelial cells. Thrombin- and activated protein C-mediated PAR-1 activation have unique effects on tumor cell biology. SUMMARY: Background Multiple studies have implicated protease-activated receptor-1 (PAR-1), a G-protein-coupled receptor activated by proteolytic cleavage of its N-terminus, as one target coupling thrombin-mediated proteolysis to tumor progression. Objective To analyze the role of PAR-1 in the setting of two distinct spontaneously developing tumor models in mice. Methods We interbred PAR-1-deficient mice with Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, which spontaneously develop prostate tumors, and adenomatous polyposis coli Min (APC ) mice, which spontaneously develop intestinal adenomas. Results Analyses of TRAMP mice with advanced disease (30 weeks) revealed that PAR-1 deficiency resulted in significantly larger and more aggressive prostate tumors. Prostates collected at an earlier time point (12 weeks of age) revealed that PAR-1 promotes apoptosis in transformed epithelia. In vitro analyses of TRAMP-derived cells revealed that activated protein C-mediated PAR-1 cleavage can induce tumor cell apoptosis, suggesting that tumor cell-intrinsic PAR-1 functions can limit tumor progression. Paralleling results in TRAMP mice, PAR-1-deficient APC mice developed three-fold more adenomas than PAR-1-expressing mice, and the adenomas that formed were significantly larger. Moreover, loss of PAR-1 expression was shown to limit apoptosis in transformed intestinal epithelial cells. Conclusions Together, these results demonstrate a previously unrecognized role for PAR-1 in impeding tumor progression in vivo. These results also offer a cautionary note suggesting that long-term PAR-1 inhibition could increase malignancy risk in some contexts.

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Review of vorapaxar for the prevention of atherothrombotic events

Abstract: Use of vorapaxar may be limited due to its high potential for causing bleeding. Efficacy of vorapaxar in addition to aspirin and prasugrel or ticagrelor for the management of ACS should be studied in the future.

Cited by 14 publications

References 30 publications

Antithrombotic Agents and Cancer

Antithrombotic Agents and Cancer

Protease-activated receptor-1 (PAR-1): a promising molecular target for cancer

Protease‐activated receptor‐1 impedes prostate and intestinal tumor progression in mice

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