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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
Author
Nishiuchi, Shiori Tokushima University
Saito, Hiroumi Tokushima University
Zamami, Yoshito Tokushima University|Okayama University KAKEN Search Researchers
Miyata, Koji Tokushima University
Sakamoto, Yoshika Tokushima University
Fukunaga, Kimiko Tokushima University
Ishida, Shunsuke Tokushima University
Chuma, Masayuki Asahikawa Medical University
Nawa, Hideki Shujitsu University
Kanda, Yasunari National Institute of Health Sciences
Keywords
Drug–drug interaction
Cardiology
Data analysis
Chemotherapy
Doxorubicin
Content Type
Thesis or Dissertation
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
ISSN
00142999
NCID
AA00639687
AA11527211
Publisher
Elsevier
Volume
928
Start Page
175083
Published Date
2022-05-31
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/).
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3698号
Diploma Number
甲医第1567号
Granted Date
2023-03-23
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
University Hospital
Medical Sciences