The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer
The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer
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抗精神病药氟哌噻吨是一种新型 PI3K 抑制剂和潜在的肺癌抗癌药物
DOI：
10.7150/ijbs.32625
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发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Lin, Marie Chia-mi
中科院分区：
文献类型：
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作者：
Dong, Chao;Chen, Yin;Lin, Marie Chia-mi
背景资料：磷脂酰肌醇3-激酶（PI 3 K）/AKT信号通路在肺癌中过度活化，并调节广泛的细胞过程，包括增殖、存活、血管生成和转移。因此，PI 3 K被认为是一个有前途的治疗靶点。迄今为止，PI 3 K抑制剂尚未被批准用于肺癌。近年来研究发现抗精神病药物氟哌噻吨可诱导肺癌细胞凋亡，但其抗肿瘤机制尚不清楚。方法：（1）利用idock软件模拟PI 3 K α蛋白与氟哌噻吨的分子对接。(2)通过体外激酶试验检测氟哌噻吨对PI 3 K α的抑制作用。(3)MTT法检测氟哌噻吨对NSCLC细胞株的细胞毒性。(4)我们用氟哌噻吨处理A549和H661细胞，然后通过Annexin V/PI分析来测量凋亡细胞的百分比。(5)我们研究了氟哌噻吨对PI 3 K/AKT信号通路关键蛋白表达的影响，并进一步通过Western blotting分析了PARP和caspase-3的切割。(6)采用BALB/C裸鼠皮下注射A549肺癌细胞，观察氟哌噻吨对肺癌生长的影响。结果：预测结合构象的结构分析表明，氟哌噻吨与PI 3 K α的ATP结合口袋对接。激酶试验表明，氟哌噻吨确实抑制PI 3 K α激酶活性。氟哌噻吨对肺癌细胞株A549和H661的细胞毒性呈剂量和时间依赖性。此外，氟哌噻吨比两种已知的PI 3 K抑制剂（BYL 719和BKM 120）更强地抑制AKT（T308和S473）的磷酸化及其下游靶基因Bcl-2的表达。通过PARP和caspase-3裂解测定氟哌噻吨诱导细胞凋亡。最后，氟哌噻吨显著抑制BALB/C裸鼠中A549异种移植物的生长。结论：氟哌噻吨可与PI 3 K α蛋白对接，在体内外特异性抑制PI 3 K/AKT通路，抑制肺癌细胞存活。氟哌噻吨是一种新型的PI 3 K抑制剂，作为一种老药，可能用于肺癌的治疗。
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 PI3Kα protein and flupentixol. (2) Inhibition of PI3Kα 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 PI3Kα. Kinase assays demonstrate that flupentixol indeed inhibited the PI3Kα 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 S473) 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 PI3Kα 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.