抗精神病剂flupentixol是一个新的PI3K抑制剂和潜在的抗癌治疗肺癌的药物。

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李董C,陈Y, H,杨Y,张H,柯K, XN,刘X,李L,马J,龚高频,陈C,林MC

抗精神病剂flupentixol是一个新的PI3K抑制剂和潜在的抗癌治疗肺癌的药物。

Int J Sci杂志。2019年6月2;(7):1523 - 1532。doi: 10.7150 / ijbs.32625。eCollection 2019。

PubMed ID

31337981 (在PubMed

]

文摘

背景:磷脂酰肌醇3-kinase PI3K / AKT信号通路在肺癌和hyperactivated调节范围广泛的细胞过程,包括增殖、生存、血管生成和转移。因此PI3K被认为是一种很有前途的治疗目标。到目前为止,PI3K抑制剂没有被批准用于肺癌。最近的研究表明,抗精神病剂flupentixol诱导肺癌细胞凋亡的细胞,然而flupentixol的抗肿瘤机制仍不清楚。方法:(1)idock软件模拟之间的分子对接PI3Kalpha蛋白质和flupentixol。(2)抑制的PI3Kalpha flupentixol被体外激酶化验检查。(3)flupentixol在非小细胞肺癌细胞株的细胞毒性是通过MTT实验测试。(4)我们对A549和H661细胞flupentixol然后测量膜联蛋白V /凋亡细胞的比例的π分析。(5)我们调查的影响flupentixol关键PI3K / AKT信号通路的表达蛋白,进一步分析了PARP的乳沟和caspase-3西方墨点法。(6)BALB / C裸小鼠皮下注射A549细胞评估flupentixol对肺癌的生长的影响。 Results: Structural analysis of the predicted binding conformation suggested that flupentixol docks to the ATP binding pocket of PI3Kalpha. Kinase assays demonstrate that flupentixol indeed inhibited the PI3Kalpha 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 PI3Kalpha 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.

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药物

Flupentixol