ArticleJournal of thrombosis and haemostasis : JTH2012
The tick-derived inhibitor Ixolaris prevents tissue factor signaling on tumor cells.
Article in Journal of thrombosis and haemostasis : JTH, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 40 citations in OpenAlex.
- A Kunitz-type inhibitor from tick salivary glands: A promising novel antitumor drug candidate.Frontiers in molecular biosciences · 2022Review
- Host Immune Responses to Salivary Components - A Critical Facet of Tick-Host Interactions.Frontiers in cellular and infection microbiology · 2022Review
- Insights into the Role of Tick Salivary Protease Inhibitors during Ectoparasite-Host Crosstalk.International journal of molecular sciences · 2021Review
- The sialotranscriptome of the gopher-tortoise tick, Amblyomma tuberculatum.Ticks and tick-borne diseases · 2021Article
- Development ofClinical & experimental metastasis · 2020Article
- Ticks and the effects of their saliva on growth factors involved in skin wound healing.Journal of venom research · 2020Review
- Article
- Deciphering Biological Processes at the Tick-Host Interface Opens New Strategies for Treatment of Human Diseases.Frontiers in physiology · 2019Review
- GPCR Modulation in Breast Cancer.International journal of molecular sciences · 2018Review
- Article
- Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy.Science translational medicine · 2017Article
- Therapeutic arthropods and other, largely terrestrial, folk-medicinally important invertebrates: a comparative survey and review.Journal of ethnobiology and ethnomedicine · 2017Review
- Hypoxia regulates the expression of tissue factor pathway signaling elements in a rat glioma model.Oncology letters · 2016Article
- Targeting clotting proteins in cancer therapy - progress and challenges.Thrombosis research · 2016Review
- Breast cancer phenotypes regulated by tissue factor-factor VII pathway: Possible therapeutic targets.World journal of clinical oncology · 2014Review
- Interconnections between autophagy and the coagulation cascade in hepatocellular carcinoma.Cell death & disease · 2014Article
- Activation of blood coagulation in cancer: implications for tumour progression.Bioscience reports · 2013Review
- The "Vampirome": Transcriptome and proteome analysis of the principal and accessory submaxillary glands of the vampire bat Desmodus rotundus, a vector of human rabies.Journal of proteomics · 2013Article
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Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
Abstract
backgroundTissue factor (TF) is frequently overexpressed in cancer cells and correlated with more aggressive tumor phenotypes and poor prognosis. In addition to promoting coagulation-dependent metastasis and cancer-associated thrombosis, tumor cell-expressed TF mediates direct cell signaling involving the protease-activated receptor (PAR) 2. Ixolaris is a tick-derived inhibitor of the TF-factor (F)VIIa-Xa coagulation initiation complex which blocks primary tumor growth and angiogenesis in glioblastoma and melanoma models.
methodsIn this study we address the anti-tumor effects of Ixolaris in TF-VIIa-PAR2 signaling-dependent breast cancer models, a xenograft model of highly aggressive human MDA-MB-231 mfp cells and a syngeneic model of PAR2-deficient and replete PyMT mouse mammary carcinoma cells.
resultsIxolaris potently inhibited the procoagulant activity of human MDA-MB-231mfp or murine PyMT breast cancer cells. Ixolaris blocked signaling by the ternary TF-FVIIa-FXa complex, and, surprisingly, at higher concentrations also the binary TF-FVIIa complex on MDA-MB-231 cells. We show that Ixolaris interacts with certain residues in the human VIIa protease domain that are involved in PAR2 cleavage. In contrast to human VIIa, Ixolaris was a poor inhibitor of murine TF-FVIIa signaling and did not attenuate PAR2-dependent tumor growth in a syngeneic mouse model of breast cancer progression.
conclusionThese data show that Ixolaris inhibits PAR2 cleavage specifically by human TF signaling complexes and suggest that Ixolaris may block tumor growth of human cell models with ectopic FVIIa expression through inhibition of direct TF-FVIIa-PAR2 signaling as well as its anticoagulant activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.