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The Cardioprotective Mechanism of Phenylaminoethyl Selenides (PAESe) Against Doxorubicin-Induced Cardiotoxicity Involves Frataxin

Doxorubicin (DOX) is an anthracycline cancer chemotherapeutic that exhibits cumulative dose-limiting cardiotoxicity and limits its clinical utility. DOX treatment results in the development of morbid cardiac hypertrophy that progresses to congestive heart failure and death. Recent evidence suggests...

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Autores principales: Fu, Xiaoyu, Eggert, Mathew, Yoo, Sieun, Patel, Nikhil, Zhong, Juming, Steinke, Ian, Govindarajulu, Manoj, Turumtay, Emine Akyuz, Mouli, Shravanthi, Panizzi, Peter, Beyers, Ronald, Denney, Thomas, Arnold, Robert, Amin, Rajesh H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072348/
https://www.ncbi.nlm.nih.gov/pubmed/33912028
http://dx.doi.org/10.3389/fphar.2020.574656
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author Fu, Xiaoyu
Eggert, Mathew
Yoo, Sieun
Patel, Nikhil
Zhong, Juming
Steinke, Ian
Govindarajulu, Manoj
Turumtay, Emine Akyuz
Mouli, Shravanthi
Panizzi, Peter
Beyers, Ronald
Denney, Thomas
Arnold, Robert
Amin, Rajesh H.
author_facet Fu, Xiaoyu
Eggert, Mathew
Yoo, Sieun
Patel, Nikhil
Zhong, Juming
Steinke, Ian
Govindarajulu, Manoj
Turumtay, Emine Akyuz
Mouli, Shravanthi
Panizzi, Peter
Beyers, Ronald
Denney, Thomas
Arnold, Robert
Amin, Rajesh H.
author_sort Fu, Xiaoyu
collection PubMed
description Doxorubicin (DOX) is an anthracycline cancer chemotherapeutic that exhibits cumulative dose-limiting cardiotoxicity and limits its clinical utility. DOX treatment results in the development of morbid cardiac hypertrophy that progresses to congestive heart failure and death. Recent evidence suggests that during the development of DOX mediated cardiac hypertrophy, mitochondrial energetics are severely compromised, thus priming the cardiomyocyte for failure. To mitigate cumulative dose (5 mg/kg, QIW x 4 weeks with 2 weeks recovery) dependent DOX, mediated cardiac hypertrophy, we applied an orally active selenium based compound termed phenylaminoethyl selenides (PAESe) (QIW 10 mg/kg x 5) to our animal model and observed that PAESe attenuates DOX-mediated cardiac hypertrophy in athymic mice, as observed by MRI analysis. Mechanistically, we demonstrated that DOX impedes the stability of the iron-sulfur cluster biogenesis protein Frataxin (FXN) (0.5 fold), resulting in enhanced mitochondrial free iron accumulation (2.5 fold) and reduced aconitase activity (0.4 fold). Our findings further indicate that PAESe prevented the reduction of FXN levels and the ensuing elevation of mitochondrial free iron levels. PAESe has been shown to have anti-oxidative properties in part, by regeneration of glutathione levels. Therefore, we observed that PAESe can mitigate DOX mediated cardiac hypertrophy by enhancing glutathione activity (0.4 fold) and inhibiting ROS formation (1.8 fold). Lastly, we observed that DOX significantly reduced cellular respiration (basal (5%) and uncoupled (10%)) in H9C2 cardiomyoblasts and that PAESe protects against the DOX-mediated attenuation of cellular respiration. In conclusion, the current study determined the protective mechanism of PAESe against DOX mediated myocardial damage and that FXN is implicitly involved in DOX-mediated cardiotoxicity.
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spelling pubmed-80723482021-04-27 The Cardioprotective Mechanism of Phenylaminoethyl Selenides (PAESe) Against Doxorubicin-Induced Cardiotoxicity Involves Frataxin Fu, Xiaoyu Eggert, Mathew Yoo, Sieun Patel, Nikhil Zhong, Juming Steinke, Ian Govindarajulu, Manoj Turumtay, Emine Akyuz Mouli, Shravanthi Panizzi, Peter Beyers, Ronald Denney, Thomas Arnold, Robert Amin, Rajesh H. Front Pharmacol Pharmacology Doxorubicin (DOX) is an anthracycline cancer chemotherapeutic that exhibits cumulative dose-limiting cardiotoxicity and limits its clinical utility. DOX treatment results in the development of morbid cardiac hypertrophy that progresses to congestive heart failure and death. Recent evidence suggests that during the development of DOX mediated cardiac hypertrophy, mitochondrial energetics are severely compromised, thus priming the cardiomyocyte for failure. To mitigate cumulative dose (5 mg/kg, QIW x 4 weeks with 2 weeks recovery) dependent DOX, mediated cardiac hypertrophy, we applied an orally active selenium based compound termed phenylaminoethyl selenides (PAESe) (QIW 10 mg/kg x 5) to our animal model and observed that PAESe attenuates DOX-mediated cardiac hypertrophy in athymic mice, as observed by MRI analysis. Mechanistically, we demonstrated that DOX impedes the stability of the iron-sulfur cluster biogenesis protein Frataxin (FXN) (0.5 fold), resulting in enhanced mitochondrial free iron accumulation (2.5 fold) and reduced aconitase activity (0.4 fold). Our findings further indicate that PAESe prevented the reduction of FXN levels and the ensuing elevation of mitochondrial free iron levels. PAESe has been shown to have anti-oxidative properties in part, by regeneration of glutathione levels. Therefore, we observed that PAESe can mitigate DOX mediated cardiac hypertrophy by enhancing glutathione activity (0.4 fold) and inhibiting ROS formation (1.8 fold). Lastly, we observed that DOX significantly reduced cellular respiration (basal (5%) and uncoupled (10%)) in H9C2 cardiomyoblasts and that PAESe protects against the DOX-mediated attenuation of cellular respiration. In conclusion, the current study determined the protective mechanism of PAESe against DOX mediated myocardial damage and that FXN is implicitly involved in DOX-mediated cardiotoxicity. Frontiers Media S.A. 2021-04-12 /pmc/articles/PMC8072348/ /pubmed/33912028 http://dx.doi.org/10.3389/fphar.2020.574656 Text en Copyright © 2021 Fu, Eggert, Yoo, Patel, Zhong, Steinke, Govindarajulu, Turumtay, Mouli, Panizzi, Beyers, Denney, Arnold and Amin. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Fu, Xiaoyu
Eggert, Mathew
Yoo, Sieun
Patel, Nikhil
Zhong, Juming
Steinke, Ian
Govindarajulu, Manoj
Turumtay, Emine Akyuz
Mouli, Shravanthi
Panizzi, Peter
Beyers, Ronald
Denney, Thomas
Arnold, Robert
Amin, Rajesh H.
The Cardioprotective Mechanism of Phenylaminoethyl Selenides (PAESe) Against Doxorubicin-Induced Cardiotoxicity Involves Frataxin
title The Cardioprotective Mechanism of Phenylaminoethyl Selenides (PAESe) Against Doxorubicin-Induced Cardiotoxicity Involves Frataxin
title_full The Cardioprotective Mechanism of Phenylaminoethyl Selenides (PAESe) Against Doxorubicin-Induced Cardiotoxicity Involves Frataxin
title_fullStr The Cardioprotective Mechanism of Phenylaminoethyl Selenides (PAESe) Against Doxorubicin-Induced Cardiotoxicity Involves Frataxin
title_full_unstemmed The Cardioprotective Mechanism of Phenylaminoethyl Selenides (PAESe) Against Doxorubicin-Induced Cardiotoxicity Involves Frataxin
title_short The Cardioprotective Mechanism of Phenylaminoethyl Selenides (PAESe) Against Doxorubicin-Induced Cardiotoxicity Involves Frataxin
title_sort cardioprotective mechanism of phenylaminoethyl selenides (paese) against doxorubicin-induced cardiotoxicity involves frataxin
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072348/
https://www.ncbi.nlm.nih.gov/pubmed/33912028
http://dx.doi.org/10.3389/fphar.2020.574656
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