Investigation of drugs for the prevention of doxorubicin-induced cardiac events using big data analysis

• Material Type: 博士論文
• Title: Investigation of drugs for the prevention of doxorubicin-induced cardiac events using big data analysis
• Author/Editor: Nishiuchi, Shiori; Yagi, Kenta; Saito, Hiroumi; Zamami, Yoshito; Niimura, Takahiro; Miyata, Koji; Sakamoto, Yoshika; Fukunaga, Kimiko; Ishida, Shunsuke; Hamano, Hirofumi; Aizawa, Fuka; Goda, Mitsuhiro; Chuma, Masayuki; Izawa-Ishizawa, Yuki; Nawa, Hideki; Yanagawa, Hiroaki; Kanda, Yasunari; Ishizawa, Keisuke
• Author Heading: Nishiuchi, Shiori; Yagi, Kenta; Saito, Hiroumi; Zamami, Yoshito; Niimura, Takahiro; Miyata, Koji; Sakamoto, Yoshika; Fukunaga, Kimiko; Ishida, Shunsuke; Hamano, Hirofumi; Aizawa, Fuka; Goda, Mitsuhiro; Chuma, Masayuki; Izawa-Ishizawa, Yuki; Nawa, Hideki; Yanagawa, Hiroaki; Kanda, Yasunari; Ishizawa, Keisuke
• Publication, Distribution, etc.: Elsevier
• Publication Date: 2022-05-31
• Publication Date (W3CDTF): 2022-05-31
• Alternative Title: 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
• Periodical title: European Journal of Pharmacology
• No. or year of volume/issue: 928
• Volume: 928
• Pages: 175083-
• ISSN (Periodical Title): ISSN : 0014-2999
• Degree grantor/type: 徳島大学
• Date Granted: 2023-03-23
• Dissertation Number: 甲第3698号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: Drug–drug interaction; Cardiology; Data analysis; Chemotherapy; Doxorubicin
• Target Audience: 一般
• Note (General): 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.
• Access Restrictions: インターネット公開
• Rights (production): This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
• Related Material (DOI): 10.1016/j.ejphar.2022.175083
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

Table of Contents

http://repo.lib.tokushima-u.ac.jp/files/public/11/117365/20230601103504759368/k3698_abstract.pdf fulltext

http://repo.lib.tokushima-u.ac.jp/files/public/11/117365/2023060110350548479/k3698_review.pdf fulltext

http://repo.lib.tokushima-u.ac.jp/files/public/11/117365/20230601103505303882/k3698_fulltext.pdf fulltext