Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model

Detalhes bibliográficos
Autor(a) principal: Brandão, Sofia Reis
Data de Publicação: 2021
Outros Autores: Reis-Mendes, Ana, Domingues, Pedro, Duarte, José Alberto, Bastos, Maria Lourdes, Carvalho, Félix, Ferreira, Rita, Costa, Vera Marisa
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10773/37200
Resumo: Current cancer therapies are successfully increasing the lifespan of cancer patients. Nevertheless, cardiotoxicity is a serious chemotherapy-induced adverse side effect. Doxorubicin (DOX) and mitoxantrone (MTX) are cardiotoxic anticancer agents, whose toxicological mechanisms are still to be identified. This study focused on DOX and MTX's cardiac mitochondrial damage and their molecular mechanisms. As a hypothesis, we also sought to compare the cardiac modulation caused by 9 mg/kg of DOX or 6 mg/kg of MTX in young adult mice (3 months old) with old control mice (aged control, 18-20 months old) to determine if DOX- and MTX-induced damage had common links with the aging process. Cardiac homogenates and enriched mitochondrial fractions were prepared from treated and control animals and analyzed by immunoblotting and enzymatic assays. Enriched mitochondrial fractions were also characterized by mass spectrometry-based proteomics. Data obtained showed a decrease in mitochondrial density in young adults treated with DOX or MTX and aged control, as assessed by citrate synthase (CS) activity. Furthermore, aged control had increased expression of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and manganese superoxide dismutase (MnSOD). Regarding the enriched mitochondrial fractions, DOX and MTX led to downregulation of proteins related to oxidative phosphorylation, fatty acid oxidation, amino acid metabolic process, and tricarboxylic acid cycle. MTX had a greater impact on malate dehydrogenase (MDH2) and pyruvate dehydrogenase E1 component subunit α (PDHA1). No significant proteomic changes were observed in the enriched mitochondrial fractions of aged control when compared to young control. To conclude, DOX and MTX promoted changes in several mitochondrial-related proteins in young adult mice, but none resembling the aged phenotype.
id RCAP_824a3ce52d176564e34f2e70f441039c
oai_identifier_str oai:ria.ua.pt:10773/37200
network_acronym_str RCAP
network_name_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository_id_str 7160
spelling Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine modelCardiotoxicityMitochondria dynamicsDoxorubicinMitoxantroneAgingCurrent cancer therapies are successfully increasing the lifespan of cancer patients. Nevertheless, cardiotoxicity is a serious chemotherapy-induced adverse side effect. Doxorubicin (DOX) and mitoxantrone (MTX) are cardiotoxic anticancer agents, whose toxicological mechanisms are still to be identified. This study focused on DOX and MTX's cardiac mitochondrial damage and their molecular mechanisms. As a hypothesis, we also sought to compare the cardiac modulation caused by 9 mg/kg of DOX or 6 mg/kg of MTX in young adult mice (3 months old) with old control mice (aged control, 18-20 months old) to determine if DOX- and MTX-induced damage had common links with the aging process. Cardiac homogenates and enriched mitochondrial fractions were prepared from treated and control animals and analyzed by immunoblotting and enzymatic assays. Enriched mitochondrial fractions were also characterized by mass spectrometry-based proteomics. Data obtained showed a decrease in mitochondrial density in young adults treated with DOX or MTX and aged control, as assessed by citrate synthase (CS) activity. Furthermore, aged control had increased expression of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and manganese superoxide dismutase (MnSOD). Regarding the enriched mitochondrial fractions, DOX and MTX led to downregulation of proteins related to oxidative phosphorylation, fatty acid oxidation, amino acid metabolic process, and tricarboxylic acid cycle. MTX had a greater impact on malate dehydrogenase (MDH2) and pyruvate dehydrogenase E1 component subunit α (PDHA1). No significant proteomic changes were observed in the enriched mitochondrial fractions of aged control when compared to young control. To conclude, DOX and MTX promoted changes in several mitochondrial-related proteins in young adult mice, but none resembling the aged phenotype.Elsevier2023-04-20T08:06:34Z2021-07-01T00:00:00Z2021-07info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10773/37200eng0300-483X10.1016/j.tox.2021.152852Brandão, Sofia ReisReis-Mendes, AnaDomingues, PedroDuarte, José AlbertoBastos, Maria LourdesCarvalho, FélixFerreira, RitaCosta, Vera Marisainfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-02-22T12:11:45Zoai:ria.ua.pt:10773/37200Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:07:49.758701Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model
title Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model
spellingShingle Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model
Brandão, Sofia Reis
Cardiotoxicity
Mitochondria dynamics
Doxorubicin
Mitoxantrone
Aging
title_short Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model
title_full Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model
title_fullStr Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model
title_full_unstemmed Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model
title_sort Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model
author Brandão, Sofia Reis
author_facet Brandão, Sofia Reis
Reis-Mendes, Ana
Domingues, Pedro
Duarte, José Alberto
Bastos, Maria Lourdes
Carvalho, Félix
Ferreira, Rita
Costa, Vera Marisa
author_role author
author2 Reis-Mendes, Ana
Domingues, Pedro
Duarte, José Alberto
Bastos, Maria Lourdes
Carvalho, Félix
Ferreira, Rita
Costa, Vera Marisa
author2_role author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Brandão, Sofia Reis
Reis-Mendes, Ana
Domingues, Pedro
Duarte, José Alberto
Bastos, Maria Lourdes
Carvalho, Félix
Ferreira, Rita
Costa, Vera Marisa
dc.subject.por.fl_str_mv Cardiotoxicity
Mitochondria dynamics
Doxorubicin
Mitoxantrone
Aging
topic Cardiotoxicity
Mitochondria dynamics
Doxorubicin
Mitoxantrone
Aging
description Current cancer therapies are successfully increasing the lifespan of cancer patients. Nevertheless, cardiotoxicity is a serious chemotherapy-induced adverse side effect. Doxorubicin (DOX) and mitoxantrone (MTX) are cardiotoxic anticancer agents, whose toxicological mechanisms are still to be identified. This study focused on DOX and MTX's cardiac mitochondrial damage and their molecular mechanisms. As a hypothesis, we also sought to compare the cardiac modulation caused by 9 mg/kg of DOX or 6 mg/kg of MTX in young adult mice (3 months old) with old control mice (aged control, 18-20 months old) to determine if DOX- and MTX-induced damage had common links with the aging process. Cardiac homogenates and enriched mitochondrial fractions were prepared from treated and control animals and analyzed by immunoblotting and enzymatic assays. Enriched mitochondrial fractions were also characterized by mass spectrometry-based proteomics. Data obtained showed a decrease in mitochondrial density in young adults treated with DOX or MTX and aged control, as assessed by citrate synthase (CS) activity. Furthermore, aged control had increased expression of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and manganese superoxide dismutase (MnSOD). Regarding the enriched mitochondrial fractions, DOX and MTX led to downregulation of proteins related to oxidative phosphorylation, fatty acid oxidation, amino acid metabolic process, and tricarboxylic acid cycle. MTX had a greater impact on malate dehydrogenase (MDH2) and pyruvate dehydrogenase E1 component subunit α (PDHA1). No significant proteomic changes were observed in the enriched mitochondrial fractions of aged control when compared to young control. To conclude, DOX and MTX promoted changes in several mitochondrial-related proteins in young adult mice, but none resembling the aged phenotype.
publishDate 2021
dc.date.none.fl_str_mv 2021-07-01T00:00:00Z
2021-07
2023-04-20T08:06:34Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10773/37200
url http://hdl.handle.net/10773/37200
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 0300-483X
10.1016/j.tox.2021.152852
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
_version_ 1799137732457398272