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The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer 期刊论文

编号：

c2cbb6fd-090f-4db7-8f27-52a219486d37
作者：

Dong, Chao(董超)#^[1]Chen, Yin#^[2]Li, Hongjian^[3,4]Yang, Yi(杨毅)^[5]Zhang, Hongtao(张洪涛)#^[6]Ke, Kunbin(柯坤彬)^[2]Shi, XiNan^[7];Liu, Xu(刘旭)^[8]Li, Ling(李玲)^[8]Ma, Jing(马静)^[9]Kung, HsiangFu(孔祥复)^[8]Chen, Ceshi(陈策实)*^[10]Lin, Marie Chiami*^[11]
语种：

英文
期刊：

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES ISSN：1449-2288 2019 年 15 卷 7 期 (1523 - 1532)
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关键词：

Flupentixol PI3K inhibitor PI3K alpha Lung cancer
摘要：

Background: The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is hyperactivated in lung cancer and regulates a broad range of cellular processes, including proliferation, survival, angiogenesis, and metastasis. Thus PI3K is considered a promising target for therapy. To date, PI3K inhibitors have not been approved for lung cancer. Recent studies showed that the antipsychotic agent flupentixol induced apoptosis of lung cancer cell, however the anti-tumor mechanism of flupentixol remains unclear.
Methods: (1) The idock software simulated the molecular docking between the PI3K alpha protein and flupentixol. (2) Inhibition of PI3K alpha by the flupentixol was examined by in vitro kinase assays. (3) The cytotoxicity of flupentixol on the NSCLC cell lines was tested by MTT assays. (4) We treated A549 and H661 cells with flupentixol and then measured the percentage of apoptotic cells by the Annexin V/PI analysis. (5) We investigated the effect of flupentixol on the expression of critical PI3K/AKT signaling pathway proteins, further analyzed on the cleavage of PARP and caspase-3 by Western blotting. (6) BALB/C nude mice were subcutaneously injected with A549 cells to evaluate the effect of flupentixol on the growth of lung carcinoma.
Results: Structural analysis of the predicted binding conformation suggested that flupentixol docks to the ATP binding pocket of PI3K alpha. Kinase assays demonstrate that flupentixol indeed inhibited the PI3K alpha kinase activity. Flupentixol exhibited cytotoxicity in lung cancer cell lines A549 and H661 in a dose- and time-dependent manner. Furthermore, flupentixol more strongly inhibited the phosphorylation of AKT (T308 and 5473) and the expression of its downstream target gene Bcl-2 than two known PI3K inhibitors (BYL719 and BKM120). Flupentixol induced apoptosis as measured by PARP and caspase-3 cleavage. Finally, flupentixol significantly suppressed A549 xenograft growth in BALB/C nude mice.
Conclusions: Flupentixol could be docked to the PI3K alpha protein and specifically inhibit the PI3K/AKT pathway and survival of lung cancer cells in vitro and in vivo. As an old drug, flupentixol is a new PI3K inhibitor that may be used for the treatment of lung cancers.
推荐引用方式
GB/T 7714：

Dong Chao,Chen Yin,Li Hongjian, et al. The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer [J].INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES,2019,15(7):1523-1532.
APA：

Dong Chao,Chen Yin,Li Hongjian,Yang Yi,&Lin Marie Chia-mi.(2019).The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer .INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES,15(7):1523-1532.
MLA：

Dong Chao, et al. "The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer" .INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES 15,7(2019):1523-1532.
入库时间：

2020/4/13 14:36:23
更新时间：

2020/4/13 14:36:23
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