A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors.
A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors.
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DOI：
10.1158/2159-8290.cd-13-0183
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发表时间：
2013-12
期刊：
影响因子：
28.2
通讯作者：
Sage J
中科院分区：
文献类型：
--
作者：
Jahchan NS;Dudley JT;Mazur PK;Flores N;Yang D;Palmerton A;Zmoos AF;Vaka D;Tran KQ;Zhou M;Krasinska K;Riess JW;Neal JW;Khatri P;Park KS;Butte AJ;Sage J
小细胞肺癌（SCLC）是一种侵袭性神经内分泌肺癌亚型，死亡率很高。我们使用系统的药物重新定位生物信息学方法查询大量基因表达谱，以确定 FDA 批准的治疗 SCLC 的候选药物。我们发现，三环类抗抑郁药和相关分子可有效诱导培养的化疗和化疗耐药 SCLC 细胞、移植到免疫功能低下小鼠体内的小鼠和人类 SCLC 肿瘤以及来自人类 SCLC 小鼠模型的内源性肿瘤的细胞凋亡。这些候选药物至少部分是通过破坏涉及神经递质及其 G 蛋白偶联受体的自分泌生存信号来激活应激途径并诱导 SCLC 细胞死亡。候选药物可抑制其他神经内分泌肿瘤的生长，包括胰腺神经内分泌肿瘤和默克尔细胞癌。这些实验确定了新的靶向策略，可以通过重新利用已批准的药物来对神经内分泌肿瘤患者进行快速评估。
Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate FDA-approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs.