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ID 117365
タイトル別表記
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
著者
西内, 栞 徳島大学大学院医学研究科(医学専攻)
Saito, Hiroumi Tokushima University
座間味, 義人 Tokushima University|Okayama University KAKEN研究者をさがす
Miyata, Koji Tokushima University
Sakamoto, Yoshika Tokushima University
Fukunaga, Kimiko Tokushima University
Ishida, Shunsuke Tokushima University
濱野, 裕章 Tokushima University|Okayama University KAKEN研究者をさがす
中馬, 真幸 Asahikawa Medical University
Nawa, Hideki Shujitsu University
Kanda, Yasunari National Institute of Health Sciences
キーワード
Drug–drug interaction
Cardiology
Data analysis
Chemotherapy
Doxorubicin
資料タイプ
学位論文
抄録
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.
掲載誌名
European Journal of Pharmacology
ISSN
00142999
cat書誌ID
AA00639687
AA11527211
出版者
Elsevier
928
開始ページ
175083
発行日
2022-05-31
備考
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。
権利情報
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3698号
学位記番号
甲医第1567号
学位授与年月日
2023-03-23
学位名
博士(医学)
学位授与機関
徳島大学
部局
病院
医学系