Chemical screening identifies the β-Carboline alkaloid harmine to be synergistically lethal with doxorubicin
Chemical screening identifies the β-Carboline alkaloid harmine to be synergistically lethal with doxorubicin
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DOI：
10.1016/j.mad.2016.04.012
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发表时间：
2017-01-01
影响因子：
5.3
通讯作者：
El-Kharnisy, Sherif F.
中科院分区：
文献类型：
--
作者：
Atteya, Reham;Ashour, Mohamed E.;El-Kharnisy, Sherif F.
尽管多柔比星是几种类型癌症的无价化疗剂，但其年龄相关和剂量依赖性心脏毒性阻碍了其临床应用。已提出将右雷佐生作为心脏保护剂联合给药，但最近的研究表明其减弱了多柔比星诱导的抗肿瘤活性。由于天然来源的化合物为药物发现提供了丰富的领域，因此我们着手鉴定推定的天然化合物，以期减轻或最小化阿霉素的心脏毒性。我们鉴定了DYRK1A激酶抑制剂骆驼蓬碱，其磷酸化在阿尔茨海默病中失调的Tau，作为无毒剂量的阿霉素诱导的细胞死亡的增效剂。这些观察结果表明，去氢骆驼蓬碱或靶向DYRK1A激酶的其他化合物可以提供新的治疗机会来抑制多柔比星年龄相关的和剂量依赖性的心脏毒性。(C)2016作者（S）出版社：Elsevier爱尔兰Ltd.
Despite being an invaluable chemotherapeutic agent for several types of cancer, the clinical utility of doxorubicin is hampered by its age-related and dose-dependent cardiotoxicity. Co-administration of dexrazoxane as a cardioprotective agent has been proposed, however recent studies suggest that it attenuates doxorubicin-induced antitumor activity. Since compounds of natural origin present a rich territory for drug discovery, we set out to identify putative natural compounds with the view to mitigate or minimize doxorubicin cardiotoxicity. We identify the DYRKIA kinase inhibitor harmine, which phosphorylates Tau that is deregulated in Alzheimer's disease, as a potentiator of cell death induced by non-toxic doses of doxorubicin. These observations suggest that harmine or other compounds that target the DYRKIA kinase my offer a new therapeutic opportunity to suppress doxorubicin age-related and dose-dependent cardiotoxicity. (C) 2016 The Author(s). Published by Elsevier Ireland Ltd.