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Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice
BACKGROUND: Doxorubicin (DOX) is widely used as an effective chemotherapeutic agent for cancers; however, DOX induces cardiac toxicity, called DOX-induced cardiomyopathy. Although DOX-induced cardiomyopathy is known to be associated with a high cumulative dose of DOX, the mechanisms of its long-term...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103594/ https://www.ncbi.nlm.nih.gov/pubmed/33962676 http://dx.doi.org/10.1186/s40360-021-00495-w |
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author | Furihata, Takaaki Maekawa, Satoshi Takada, Shingo Kakutani, Naoya Nambu, Hideo Shirakawa, Ryosuke Yokota, Takashi Kinugawa, Shintaro |
author_facet | Furihata, Takaaki Maekawa, Satoshi Takada, Shingo Kakutani, Naoya Nambu, Hideo Shirakawa, Ryosuke Yokota, Takashi Kinugawa, Shintaro |
author_sort | Furihata, Takaaki |
collection | PubMed |
description | BACKGROUND: Doxorubicin (DOX) is widely used as an effective chemotherapeutic agent for cancers; however, DOX induces cardiac toxicity, called DOX-induced cardiomyopathy. Although DOX-induced cardiomyopathy is known to be associated with a high cumulative dose of DOX, the mechanisms of its long-term effects have not been completely elucidated. Pioglitazone (Pio) is presently contraindicated in patients with symptomatic heart failure owing to the side effects. The concept of drug repositioning led us to hypothesize the potential effects of Pio as a premedication before DOX treatment, and to analyze this hypothesis in mice. METHODS: First, for the hyperacute (day 1) and acute (day 7) DOX-induced dysfunction models, mice were fed a standard diet with or without 0.02% (wt/wt) Pio for 5 days before DOX treatment (15 mg/kg body weight [BW] via intraperitoneal [i.p.] administration). The following 3 treatment groups were analyzed: standard diet + vehicle (Vehicle), standard diet + DOX (DOX), and Pio + DOX. Next, for the chronic model (day 35), the mice were administrated DOX once a week for 5 weeks (5 mg/kg BW/week, i.p.). RESULTS: In the acute phase after DOX treatment, the percent fractional shortening of the left ventricle (LV) was significantly decreased in DOX mice. This cardiac malfunction was improved in Pio + DOX mice. In the chronic phase, we observed that LV function was preserved in Pio + DOX mice. CONCLUSIONS: Our findings may provide a new pathophysiological explanation by which Pio plays a role in the treatment of DOX-induced cardiomyopathy, but the molecular links between Pio and DOX-induced LV dysfunction remain largely elusive. |
format | Online Article Text |
id | pubmed-8103594 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-81035942021-05-10 Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice Furihata, Takaaki Maekawa, Satoshi Takada, Shingo Kakutani, Naoya Nambu, Hideo Shirakawa, Ryosuke Yokota, Takashi Kinugawa, Shintaro BMC Pharmacol Toxicol Research BACKGROUND: Doxorubicin (DOX) is widely used as an effective chemotherapeutic agent for cancers; however, DOX induces cardiac toxicity, called DOX-induced cardiomyopathy. Although DOX-induced cardiomyopathy is known to be associated with a high cumulative dose of DOX, the mechanisms of its long-term effects have not been completely elucidated. Pioglitazone (Pio) is presently contraindicated in patients with symptomatic heart failure owing to the side effects. The concept of drug repositioning led us to hypothesize the potential effects of Pio as a premedication before DOX treatment, and to analyze this hypothesis in mice. METHODS: First, for the hyperacute (day 1) and acute (day 7) DOX-induced dysfunction models, mice were fed a standard diet with or without 0.02% (wt/wt) Pio for 5 days before DOX treatment (15 mg/kg body weight [BW] via intraperitoneal [i.p.] administration). The following 3 treatment groups were analyzed: standard diet + vehicle (Vehicle), standard diet + DOX (DOX), and Pio + DOX. Next, for the chronic model (day 35), the mice were administrated DOX once a week for 5 weeks (5 mg/kg BW/week, i.p.). RESULTS: In the acute phase after DOX treatment, the percent fractional shortening of the left ventricle (LV) was significantly decreased in DOX mice. This cardiac malfunction was improved in Pio + DOX mice. In the chronic phase, we observed that LV function was preserved in Pio + DOX mice. CONCLUSIONS: Our findings may provide a new pathophysiological explanation by which Pio plays a role in the treatment of DOX-induced cardiomyopathy, but the molecular links between Pio and DOX-induced LV dysfunction remain largely elusive. BioMed Central 2021-05-07 /pmc/articles/PMC8103594/ /pubmed/33962676 http://dx.doi.org/10.1186/s40360-021-00495-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Furihata, Takaaki Maekawa, Satoshi Takada, Shingo Kakutani, Naoya Nambu, Hideo Shirakawa, Ryosuke Yokota, Takashi Kinugawa, Shintaro Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice |
title | Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice |
title_full | Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice |
title_fullStr | Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice |
title_full_unstemmed | Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice |
title_short | Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice |
title_sort | premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103594/ https://www.ncbi.nlm.nih.gov/pubmed/33962676 http://dx.doi.org/10.1186/s40360-021-00495-w |
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