ID | 117365 |
Title Alternative | ビッグデータ解析を用いたドキソルビシン誘導心イベントに対する予防薬の探索
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Author |
Nishiuchi, Shiori
Tokushima University
Saito, Hiroumi
Tokushima University
Niimura, Takahiro
Tokushima University
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Miyata, Koji
Tokushima University
Sakamoto, Yoshika
Tokushima University
Fukunaga, Kimiko
Tokushima University
Ishida, Shunsuke
Tokushima University
Hamano, Hirofumi
Tokushima University|Okayama University
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Aizawa, Fuka
Tokushima University
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Goda, Mitsuhiro
Tokushima University
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Chuma, Masayuki
Asahikawa Medical University
Izawa-Ishizawa, Yuki
Tokushima University
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Nawa, Hideki
Shujitsu University
Yanagawa, Hiroaki
Tokushima University
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Kanda, Yasunari
National Institute of Health Sciences
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Keywords | Drug–drug interaction
Cardiology
Data analysis
Chemotherapy
Doxorubicin
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Content Type |
Thesis or Dissertation
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Description | Aim: Doxorubicin, an anthracycline anti-tumour agent, is an essential chemotherapeutic drug; however, the adverse events associated with doxorubicin usage, including cardiotoxicity, prevent patients from continuing treatment. Here, we used databases to explore existing approved drugs with potential preventative effects against doxorubicin-induced cardiac events and examined their efficacy and mechanisms.
Methods: The Gene Expression Omnibus (GEO), Library of Integrated Network-based Cellular Signatures (LINCS), and Food and Drug Administration Adverse Events Reporting System (FAERS) databases were used to extract candidate prophylactic drugs. Mouse models of doxorubicin-induced cardiac events were generated by intraperitoneal administration of 20 mg/kg of doxorubicin on Day 1 and oral administration of prophylactic candidate drugs for 6 consecutive days beginning the day before doxorubicin administration. On Day 6, mouse hearts were extracted and examined for mRNA expression of apoptosis-related genes. Results: GEO analysis showed that doxorubicin administration upregulated 490 genes and downregulated 862 genes, and LINCS data identified sirolimus, verapamil, minoxidil, prednisolone, guanabenz, and mosapride as drugs capable of counteracting these genetic alterations. Examination of the effects of these drugs on cardiac toxicity using FAERS identified sirolimus and mosapride as new prophylactic drug candidates. In model mice, mosapride and sirolimus suppressed the Bax/Bcl-2 mRNA ratio, which is elevated in doxorubicin-induced cardiotoxicity. These drugs also suppressed the expression of inflammatory cytokines Il1b and Il6 and markers associated with myocardial fibrosis, including Lgal3 and Timp1. Conclusion: These findings suggest that doxorubicin-induced cardiac events are suppressed by the administration of mosapride and sirolimus. |
Journal Title |
European Journal of Pharmacology
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ISSN | 00142999
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NCID | AA00639687
AA11527211
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Publisher | Elsevier
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Volume | 928
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Start Page | 175083
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Published Date | 2022-05-31
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Remark | 内容要旨・審査要旨・論文本文の公開
本論文は,著者Shiori Nishiuchiの学位論文として提出され,学位審査・授与の対象となっている。 |
Rights | This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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EDB ID | |
DOI (Published Version) | |
URL ( Publisher's Version ) | |
FullText File | |
language |
eng
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TextVersion |
ETD
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MEXT report number | 甲第3698号
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Diploma Number | 甲医第1567号
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Granted Date | 2023-03-23
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Degree Name |
Doctor of Medical Science
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Grantor |
Tokushima University
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departments |
University Hospital
Medical Sciences
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