並列タイトル等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
タイトル(掲載誌)European Journal of Pharmacology
一般注記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.
著作権情報This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
関連情報(DOI)10.1016/j.ejphar.2022.175083
連携機関・データベース国立情報学研究所 : 学術機関リポジトリデータベース(IRDB)(機関リポジトリ)