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Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment

BACKGROUND: Paclitaxel is touted as an essential medicine due to its extensive use as a chemotherapeutic for various cancers and an antiproliferative agent for restenosis. Due to recent concerns related to long-term mortality, paclitaxel (PTX)-based endovascular therapy is now surrounded by controve...

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Autores principales: Zhang, Mengwei, Lotfollahzadeh, Saran, Elzinad, Nagla, Yang, Xiaosheng, Elsadawi, Murad, Gower, Adam, Belghasem, Mostafa, Shazly, Tarek, Kolachalama, Vijaya B., Chitalia, Vipul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915804/
https://www.ncbi.nlm.nih.gov/pubmed/36778300
http://dx.doi.org/10.21203/rs.3.rs-2487922/v1
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author Zhang, Mengwei
Lotfollahzadeh, Saran
Elzinad, Nagla
Yang, Xiaosheng
Elsadawi, Murad
Gower, Adam
Belghasem, Mostafa
Shazly, Tarek
Kolachalama, Vijaya B.
Chitalia, Vipul
author_facet Zhang, Mengwei
Lotfollahzadeh, Saran
Elzinad, Nagla
Yang, Xiaosheng
Elsadawi, Murad
Gower, Adam
Belghasem, Mostafa
Shazly, Tarek
Kolachalama, Vijaya B.
Chitalia, Vipul
author_sort Zhang, Mengwei
collection PubMed
description BACKGROUND: Paclitaxel is touted as an essential medicine due to its extensive use as a chemotherapeutic for various cancers and an antiproliferative agent for restenosis. Due to recent concerns related to long-term mortality, paclitaxel (PTX)-based endovascular therapy is now surrounded by controversies. OBJECTIVE: Examine the inflammatory mediators driven by the systemic administration of PTX and explore the means to suppress these effects. METHODS: RNAseq analysis, cell and mouse models. RESULTS: RNAseq analysis of primary human endothelial cells (ECs) treated with PTX demonstrated transcriptional perturbations of a set of pro-inflammatory mediators, including monocyte chemoattractant protein-1 (MCP-1) and CD137, which were validated in EC lysates. These perturbations were abrogated with dexamethasone, a prototypic anti-inflammatory compound. The media of ECs pre-treated with PTX showed a significant increase in MCP-1 levels, which were reverted to baseline levels with DEX treatment. A group of mice harvested at different time points after PTX injection were analyzed for immediate and delayed effects of PTX. A 3-fold increase in MCP-1 was noted in blood and aortic ECs after 12 hours of PTX treatment. Similar changes in CD137 and downstream mediators such as tissue factor, VCAM-1 and E-selectin were noted in aortic ECs. CONCLUSIONS: Our study shows that systemic PTX exposure upregulates atherothrombotic markers, and co-delivery of DEX can subdue the untoward toxic effects. Long-term studies are needed to probe the mechanisms driving systemic complications of PTX-based therapies and evaluate the clinical potential of DEX to mitigate risk.
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spelling pubmed-99158042023-02-11 Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment Zhang, Mengwei Lotfollahzadeh, Saran Elzinad, Nagla Yang, Xiaosheng Elsadawi, Murad Gower, Adam Belghasem, Mostafa Shazly, Tarek Kolachalama, Vijaya B. Chitalia, Vipul Res Sq Article BACKGROUND: Paclitaxel is touted as an essential medicine due to its extensive use as a chemotherapeutic for various cancers and an antiproliferative agent for restenosis. Due to recent concerns related to long-term mortality, paclitaxel (PTX)-based endovascular therapy is now surrounded by controversies. OBJECTIVE: Examine the inflammatory mediators driven by the systemic administration of PTX and explore the means to suppress these effects. METHODS: RNAseq analysis, cell and mouse models. RESULTS: RNAseq analysis of primary human endothelial cells (ECs) treated with PTX demonstrated transcriptional perturbations of a set of pro-inflammatory mediators, including monocyte chemoattractant protein-1 (MCP-1) and CD137, which were validated in EC lysates. These perturbations were abrogated with dexamethasone, a prototypic anti-inflammatory compound. The media of ECs pre-treated with PTX showed a significant increase in MCP-1 levels, which were reverted to baseline levels with DEX treatment. A group of mice harvested at different time points after PTX injection were analyzed for immediate and delayed effects of PTX. A 3-fold increase in MCP-1 was noted in blood and aortic ECs after 12 hours of PTX treatment. Similar changes in CD137 and downstream mediators such as tissue factor, VCAM-1 and E-selectin were noted in aortic ECs. CONCLUSIONS: Our study shows that systemic PTX exposure upregulates atherothrombotic markers, and co-delivery of DEX can subdue the untoward toxic effects. Long-term studies are needed to probe the mechanisms driving systemic complications of PTX-based therapies and evaluate the clinical potential of DEX to mitigate risk. American Journal Experts 2023-01-30 /pmc/articles/PMC9915804/ /pubmed/36778300 http://dx.doi.org/10.21203/rs.3.rs-2487922/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. https://creativecommons.org/licenses/by/4.0/License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License (https://creativecommons.org/licenses/by/4.0/)
spellingShingle Article
Zhang, Mengwei
Lotfollahzadeh, Saran
Elzinad, Nagla
Yang, Xiaosheng
Elsadawi, Murad
Gower, Adam
Belghasem, Mostafa
Shazly, Tarek
Kolachalama, Vijaya B.
Chitalia, Vipul
Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment
title Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment
title_full Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment
title_fullStr Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment
title_full_unstemmed Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment
title_short Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment
title_sort alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915804/
https://www.ncbi.nlm.nih.gov/pubmed/36778300
http://dx.doi.org/10.21203/rs.3.rs-2487922/v1
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