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Synergistic cardioprotective effects of melatonin and deferoxamine through the improvement of ferritinophagy in doxorubicin-induced acute cardiotoxicity

Ferritinophagy is one of the most recent molecular mechanisms affecting cardiac function. In addition, it is one of the pathways by which doxorubicin, one of the anticancer drugs commonly used, negatively impacts the cardiac muscle, leading to cardiac function impairment. This side effect limits the...

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Autores principales: Hanna, Mira, Seddiek, Hanan, Aboulhoda, Basma Emad, Morcos, George N. B., Akabawy, Ahmed M. A., Elbaset, Marawan Abd, Ibrahim, Abdelsatar Abdelsatar, Khalifa, Mohamed Mansour, Khalifah, Ibtesam Mahmoud, Fadel, Mostafa Said, Shoukry, Tarek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9748574/
https://www.ncbi.nlm.nih.gov/pubmed/36531171
http://dx.doi.org/10.3389/fphys.2022.1050598
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author Hanna, Mira
Seddiek, Hanan
Aboulhoda, Basma Emad
Morcos, George N. B.
Akabawy, Ahmed M. A.
Elbaset, Marawan Abd
Ibrahim, Abdelsatar Abdelsatar
Khalifa, Mohamed Mansour
Khalifah, Ibtesam Mahmoud
Fadel, Mostafa Said
Shoukry, Tarek
author_facet Hanna, Mira
Seddiek, Hanan
Aboulhoda, Basma Emad
Morcos, George N. B.
Akabawy, Ahmed M. A.
Elbaset, Marawan Abd
Ibrahim, Abdelsatar Abdelsatar
Khalifa, Mohamed Mansour
Khalifah, Ibtesam Mahmoud
Fadel, Mostafa Said
Shoukry, Tarek
author_sort Hanna, Mira
collection PubMed
description Ferritinophagy is one of the most recent molecular mechanisms affecting cardiac function. In addition, it is one of the pathways by which doxorubicin, one of the anticancer drugs commonly used, negatively impacts the cardiac muscle, leading to cardiac function impairment. This side effect limits the use of doxorubicin. Iron chelators play an important role in hindering ferritinophagy. Antioxidants can also impact ferritinophagy by improving oxidative stress. In this study, it was assumed that the antioxidant function of melatonin could promote the action of deferoxamine, an iron chelator, at the level of ferritinophagy. A total of 42 male Wistar rats (150–200 g) were divided into seven groups (n = 6) which consisted of group I: control normal, group II: doxorubicin (Dox), group III: melatonin (Mel), group IV: deferoxamine (Des), group V: Mel + Dox, group VI: Des + Dox, and group VII: Mel + Des + Dox. Groups III, V and VII were orally pretreated with melatonin 20 mg/kg/day for 7 days. Groups IV, VI and VII were treated with deferoxamine at a 250 mg/kg/dose once on D4 before Dox was given. Doxorubicin was given at a 20 mg/kg ip single dose. On the 8th day, the rats were lightly anaesthetized for electrocardiography analysis and echocardiography. Serum samples were collected and then sacrificed for tissue sampling. The following biochemical assessments were carried out: PCR of NCOA4, IREB2, FTH1, SLC7A11, and GPX4; and ELISA for serum cTnI, serum transferrin, tissue GSH, and malondialdehyde. In addition, histopathological assessment of heart injury; immunostaining of caspase-3, Bax, and Bcl2; and physiological function assessment by ECG and ECHO were carried out. Doxorubicin-induced acute significant cardiac injury with increased ferritinophagy and apoptosis responded to single and combined prophylactic treatment, in which the combined treatment showed mostly the best results. In conclusion, using melatonin as an antioxidant with an iron chelator, deferoxamine, could hinder the hazardous cardiotoxic effect of doxorubicin. However, further studies are needed to detect the impact of higher doses of melatonin and deferoxamine with a prolonged treatment period.
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spelling pubmed-97485742022-12-15 Synergistic cardioprotective effects of melatonin and deferoxamine through the improvement of ferritinophagy in doxorubicin-induced acute cardiotoxicity Hanna, Mira Seddiek, Hanan Aboulhoda, Basma Emad Morcos, George N. B. Akabawy, Ahmed M. A. Elbaset, Marawan Abd Ibrahim, Abdelsatar Abdelsatar Khalifa, Mohamed Mansour Khalifah, Ibtesam Mahmoud Fadel, Mostafa Said Shoukry, Tarek Front Physiol Physiology Ferritinophagy is one of the most recent molecular mechanisms affecting cardiac function. In addition, it is one of the pathways by which doxorubicin, one of the anticancer drugs commonly used, negatively impacts the cardiac muscle, leading to cardiac function impairment. This side effect limits the use of doxorubicin. Iron chelators play an important role in hindering ferritinophagy. Antioxidants can also impact ferritinophagy by improving oxidative stress. In this study, it was assumed that the antioxidant function of melatonin could promote the action of deferoxamine, an iron chelator, at the level of ferritinophagy. A total of 42 male Wistar rats (150–200 g) were divided into seven groups (n = 6) which consisted of group I: control normal, group II: doxorubicin (Dox), group III: melatonin (Mel), group IV: deferoxamine (Des), group V: Mel + Dox, group VI: Des + Dox, and group VII: Mel + Des + Dox. Groups III, V and VII were orally pretreated with melatonin 20 mg/kg/day for 7 days. Groups IV, VI and VII were treated with deferoxamine at a 250 mg/kg/dose once on D4 before Dox was given. Doxorubicin was given at a 20 mg/kg ip single dose. On the 8th day, the rats were lightly anaesthetized for electrocardiography analysis and echocardiography. Serum samples were collected and then sacrificed for tissue sampling. The following biochemical assessments were carried out: PCR of NCOA4, IREB2, FTH1, SLC7A11, and GPX4; and ELISA for serum cTnI, serum transferrin, tissue GSH, and malondialdehyde. In addition, histopathological assessment of heart injury; immunostaining of caspase-3, Bax, and Bcl2; and physiological function assessment by ECG and ECHO were carried out. Doxorubicin-induced acute significant cardiac injury with increased ferritinophagy and apoptosis responded to single and combined prophylactic treatment, in which the combined treatment showed mostly the best results. In conclusion, using melatonin as an antioxidant with an iron chelator, deferoxamine, could hinder the hazardous cardiotoxic effect of doxorubicin. However, further studies are needed to detect the impact of higher doses of melatonin and deferoxamine with a prolonged treatment period. Frontiers Media S.A. 2022-11-30 /pmc/articles/PMC9748574/ /pubmed/36531171 http://dx.doi.org/10.3389/fphys.2022.1050598 Text en Copyright © 2022 Hanna, Seddiek, Aboulhoda, Morcos, Akabawy, Elbaset, Ibrahim, Khalifa, Khalifah, Fadel and Shoukry. 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 Physiology
Hanna, Mira
Seddiek, Hanan
Aboulhoda, Basma Emad
Morcos, George N. B.
Akabawy, Ahmed M. A.
Elbaset, Marawan Abd
Ibrahim, Abdelsatar Abdelsatar
Khalifa, Mohamed Mansour
Khalifah, Ibtesam Mahmoud
Fadel, Mostafa Said
Shoukry, Tarek
Synergistic cardioprotective effects of melatonin and deferoxamine through the improvement of ferritinophagy in doxorubicin-induced acute cardiotoxicity
title Synergistic cardioprotective effects of melatonin and deferoxamine through the improvement of ferritinophagy in doxorubicin-induced acute cardiotoxicity
title_full Synergistic cardioprotective effects of melatonin and deferoxamine through the improvement of ferritinophagy in doxorubicin-induced acute cardiotoxicity
title_fullStr Synergistic cardioprotective effects of melatonin and deferoxamine through the improvement of ferritinophagy in doxorubicin-induced acute cardiotoxicity
title_full_unstemmed Synergistic cardioprotective effects of melatonin and deferoxamine through the improvement of ferritinophagy in doxorubicin-induced acute cardiotoxicity
title_short Synergistic cardioprotective effects of melatonin and deferoxamine through the improvement of ferritinophagy in doxorubicin-induced acute cardiotoxicity
title_sort synergistic cardioprotective effects of melatonin and deferoxamine through the improvement of ferritinophagy in doxorubicin-induced acute cardiotoxicity
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9748574/
https://www.ncbi.nlm.nih.gov/pubmed/36531171
http://dx.doi.org/10.3389/fphys.2022.1050598
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