Investigation of drugs for the prevention of doxorubicin-induced cardiac events using big data analysis
Investigation of drugs for the prevention of doxorubicin-induced cardiac events using big data analysis
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DOI：
10.1016/j.ejphar.2022.175083
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发表时间：
2022-06-14
影响因子：
5
通讯作者：
Ishizawa, Keisuke
中科院分区：
文献类型：
--
作者：
Nishiuchi, Shiori;Yagi, Kenta;Ishizawa, Keisuke
目的：多柔比星是一种重要的化疗药物，是一种重要的抗肿瘤药物。然而，阿霉素的不良反应，包括心脏毒性，阻碍了患者继续治疗。方法：利用基因表达总表(GEO)、基于网络的细胞特征文库(LINCS)和美国食品和药物管理局不良事件报告系统(FAERS)数据库，提取候选预防药物。阿霉素致小鼠心脏事件模型为阿霉素20 mg/kg，第1天腹腔注射，从给药前一天开始连续6天口服预防候选药物。结果：GEO分析显示阿霉素组有490个基因表达上调，862个基因表达下调，LINCS数据显示西罗莫司、维拉帕米、米诺地尔、强的松龙、异烟肼和莫沙必利可对抗这些基因改变。使用FAERS检查这些药物对心脏毒性的影响，确定西罗莫司和莫沙必利为新的预防药物候选药物。在模型小鼠中，莫沙必利和西罗莫司抑制Bax/Bcl-2mRNA比率，该比率在阿霉素诱导的心脏毒性中升高。这些药物还抑制炎症细胞因子IL1b和IL6的表达，以及与心肌纤维化相关的标记物Lgal3和Timp1的表达。结论：莫沙必利和西罗莫司可抑制阿霉素诱导的心脏事件。
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.