RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice

Abstract Induction of thrombosis in tumor vasculature represents an appealing strategy for combating cancer. Herein, we combined unique intrinsic coagulation properties of staphylocoagulase with new acquired functional potentials introduced by genetic engineering, to generate a novel bi-functional f...

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Autores principales:	Rana Jahanban-Esfahlan, Khaled Seidi, Hassan Monhemi, Amir Daei Farshchi Adli, Babak Minofar, Peyman Zare, Davoud Farajzadeh, Safar Farajnia, Ramezan Behzadi, Mehran Mesgari Abbasi, Nosratollah Zarghami, Tahereh Javaheri
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b5881d644e7d46bf881e23c2c471dc2b
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spelling	oai:doaj.org-article:b5881d644e7d46bf881e23c2c471dc2b2021-12-02T12:32:39ZRGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice10.1038/s41598-017-05326-92045-2322https://doaj.org/article/b5881d644e7d46bf881e23c2c471dc2b2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05326-9https://doaj.org/toc/2045-2322Abstract Induction of thrombosis in tumor vasculature represents an appealing strategy for combating cancer. Herein, we combined unique intrinsic coagulation properties of staphylocoagulase with new acquired functional potentials introduced by genetic engineering, to generate a novel bi-functional fusion protein consisting of truncated coagulase (tCoa) bearing an RGD motif on its C-terminus for cancer therapy. We demonstrated that free coagulase failed to elicit any significant thrombotic activity. Conversely, RGD delivery of coagulase retained coagulase activity and afforded favorable interaction of fusion proteins with prothrombin and αvβ3 endothelial cell receptors, as verified by in silico, in vitro, and in vivo experiments. Although free coagulase elicited robust coagulase activity in vitro, only targeted coagulase (tCoa-RGD) was capable of producing extensive thrombosis, and subsequent infarction and massive necrosis of CT26 mouse colon, 4T1 mouse mammary and SKOV3 human ovarian tumors in mice. Additionally, systemic injections of lower doses of tCoa-RGD produced striking tumor growth inhibition of CT26, 4T1 and SKOV3 solid tumors in animals. Altogether, the nontoxic nature, unique shortcut mechanism, minimal effective dose, wide therapeutic window, efficient induction of thrombosis, local effects and susceptibility of human blood to coagulase suggest tCoa-RGD fusion proteins as a novel and promising anticancer therapy for human trials.Rana Jahanban-EsfahlanKhaled SeidiHassan MonhemiAmir Daei Farshchi AdliBabak MinofarPeyman ZareDavoud FarajzadehSafar FarajniaRamezan BehzadiMehran Mesgari AbbasiNosratollah ZarghamiTahereh JavaheriNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rana Jahanban-Esfahlan Khaled Seidi Hassan Monhemi Amir Daei Farshchi Adli Babak Minofar Peyman Zare Davoud Farajzadeh Safar Farajnia Ramezan Behzadi Mehran Mesgari Abbasi Nosratollah Zarghami Tahereh Javaheri RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice
description	Abstract Induction of thrombosis in tumor vasculature represents an appealing strategy for combating cancer. Herein, we combined unique intrinsic coagulation properties of staphylocoagulase with new acquired functional potentials introduced by genetic engineering, to generate a novel bi-functional fusion protein consisting of truncated coagulase (tCoa) bearing an RGD motif on its C-terminus for cancer therapy. We demonstrated that free coagulase failed to elicit any significant thrombotic activity. Conversely, RGD delivery of coagulase retained coagulase activity and afforded favorable interaction of fusion proteins with prothrombin and αvβ3 endothelial cell receptors, as verified by in silico, in vitro, and in vivo experiments. Although free coagulase elicited robust coagulase activity in vitro, only targeted coagulase (tCoa-RGD) was capable of producing extensive thrombosis, and subsequent infarction and massive necrosis of CT26 mouse colon, 4T1 mouse mammary and SKOV3 human ovarian tumors in mice. Additionally, systemic injections of lower doses of tCoa-RGD produced striking tumor growth inhibition of CT26, 4T1 and SKOV3 solid tumors in animals. Altogether, the nontoxic nature, unique shortcut mechanism, minimal effective dose, wide therapeutic window, efficient induction of thrombosis, local effects and susceptibility of human blood to coagulase suggest tCoa-RGD fusion proteins as a novel and promising anticancer therapy for human trials.
format	article
author	Rana Jahanban-Esfahlan Khaled Seidi Hassan Monhemi Amir Daei Farshchi Adli Babak Minofar Peyman Zare Davoud Farajzadeh Safar Farajnia Ramezan Behzadi Mehran Mesgari Abbasi Nosratollah Zarghami Tahereh Javaheri
author_facet	Rana Jahanban-Esfahlan Khaled Seidi Hassan Monhemi Amir Daei Farshchi Adli Babak Minofar Peyman Zare Davoud Farajzadeh Safar Farajnia Ramezan Behzadi Mehran Mesgari Abbasi Nosratollah Zarghami Tahereh Javaheri
author_sort	Rana Jahanban-Esfahlan
title	RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice
title_short	RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice
title_full	RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice
title_fullStr	RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice
title_full_unstemmed	RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice
title_sort	rgd delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/b5881d644e7d46bf881e23c2c471dc2b
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RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice

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