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

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 pro...

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Autores principales: Jahanban-Esfahlan, Rana, Seidi, Khaled, Monhemi, Hassan, Adli, Amir Daei Farshchi, Minofar, Babak, Zare, Peyman, Farajzadeh, Davoud, Farajnia, Safar, Behzadi, Ramezan, Abbasi, Mehran Mesgari, Zarghami, Nosratollah, Javaheri, Tahereh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557930/
https://www.ncbi.nlm.nih.gov/pubmed/28811469
http://dx.doi.org/10.1038/s41598-017-05326-9
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author Jahanban-Esfahlan, Rana
Seidi, Khaled
Monhemi, Hassan
Adli, Amir Daei Farshchi
Minofar, Babak
Zare, Peyman
Farajzadeh, Davoud
Farajnia, Safar
Behzadi, Ramezan
Abbasi, Mehran Mesgari
Zarghami, Nosratollah
Javaheri, Tahereh
author_facet Jahanban-Esfahlan, Rana
Seidi, Khaled
Monhemi, Hassan
Adli, Amir Daei Farshchi
Minofar, Babak
Zare, Peyman
Farajzadeh, Davoud
Farajnia, Safar
Behzadi, Ramezan
Abbasi, Mehran Mesgari
Zarghami, Nosratollah
Javaheri, Tahereh
author_sort Jahanban-Esfahlan, Rana
collection PubMed
description 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 α(v)β(3) 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.
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spelling pubmed-55579302017-08-16 RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice Jahanban-Esfahlan, Rana Seidi, Khaled Monhemi, Hassan Adli, Amir Daei Farshchi Minofar, Babak Zare, Peyman Farajzadeh, Davoud Farajnia, Safar Behzadi, Ramezan Abbasi, Mehran Mesgari Zarghami, Nosratollah Javaheri, Tahereh Sci Rep Article 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 α(v)β(3) 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. Nature Publishing Group UK 2017-08-15 /pmc/articles/PMC5557930/ /pubmed/28811469 http://dx.doi.org/10.1038/s41598-017-05326-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Jahanban-Esfahlan, Rana
Seidi, Khaled
Monhemi, Hassan
Adli, Amir Daei Farshchi
Minofar, Babak
Zare, Peyman
Farajzadeh, Davoud
Farajnia, Safar
Behzadi, Ramezan
Abbasi, Mehran Mesgari
Zarghami, Nosratollah
Javaheri, Tahereh
RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557930/
https://www.ncbi.nlm.nih.gov/pubmed/28811469
http://dx.doi.org/10.1038/s41598-017-05326-9
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