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 DYRK1A 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 DYRK1A kinase my offer a new therapeutic opportunity to suppress doxorubicin age-related and dose-dependent cardiotoxicity.

中文翻译：

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化学筛选确定了β-卡宾碱生物碱与阿霉素协同致死性。

尽管阿霉素是几种类型癌症的宝贵化学治疗剂，但阿霉素的年龄相关性和剂量依赖性心脏毒性阻碍了其临床应用。已经提出了将右雷佐生作为心脏保护剂的共同给药，但是最近的研究表明，它会减弱阿霉素诱导的抗肿瘤活性。由于天然来源的化合物为药物发现提供了广阔的领域，因此我们着手确定推定的天然化合物，以减轻或最小化阿霉素的心脏毒性。我们确定DYRK1A激酶抑制剂harmine，它使在阿尔茨海默氏病中失调的Tau磷酸化，作为无毒剂量的阿霉素诱导的细胞死亡的增强剂。