Brusatol suppresses the growth of intrahepatic cholangiocarcinoma by PI3K/Akt pathway
Brusatol suppresses the growth of intrahepatic cholangiocarcinoma by PI3K/Akt pathway
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DOI：
10.1016/j.phymed.2022.154323
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发表时间：
2022-07-17
期刊：
影响因子：
7.9
通讯作者：
Chen, Gang
中科院分区：
文献类型：
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作者：
Chen, Ziyan;He, Bangjie;Chen, Gang
背景：肝内胆管癌（ICC）是一种起病隐匿、转移复发率高、预后差的恶性肿瘤。研究治疗ICC有效药物对于临床改善患者预后具有重要意义。鸦胆子醇是从鸦胆子种子中提取的苦木素，已被证明具有抑制肿瘤转移和增殖的潜力。目前尚无关于布鲁沙醇对 ICC 的治疗作用的科学研究。我们的研究为ICC的治疗提供了一种新的策略。目的：探讨布鲁萨醇治疗对ICC的影响并阐明可能的机制。研究设计：将各种细胞功能实验和基本实验技术应用于ICC细胞系，探讨布鲁萨醇对ICC细胞的影响；这一结论在动物模型中得到进一步验证。方法：分别通过细胞功能实验、WB印迹实验和转录组测序实验验证该药物在细胞、蛋白质和RNA水平上的抗癌作用。最后利用裸鼠皮下肿瘤实验验证了实验结果。结果：结果显示，布鲁萨醇治疗后ICC细胞上皮标志物水平升高，间质标志物水平下降，抑制上皮间质转化（EMT）过程。 Brusatol 通过激活 PI3K/Akt 通路抑制 Hucc-T1 和 RBE 癌细胞增殖、诱导细胞凋亡并抑制其迁移和侵袭能力。它还抑制裸鼠Hucc-T1异种移植物的生长。结论：Brusatol通过PI3K/Akt途径抑制ICC癌细胞的增殖和EMT过程，并促进癌细胞凋亡。
Background: Intrahepatic cholangiocarcinoma (ICC) is a malignancy with a hidden onset, high metastasis recurrence rate, and poor prognosis. Research on effective drugs for ICC is important for improving the prognosis of patients in the clinic. Brusatol is a quassinoid extracted from the seeds of Brucea sumatrana and has been shown to have the potential to inhibit tumor metastasis and proliferation. There has been no scientific research on the therapeutic effect of brusatol on ICC. Our study offers a novel strategy for the therapy of ICC.Purpose: Explore effects of brusatol treatment on ICC and clarify the possible mechanism.Study Design: Various cell functional experiments and basic experimental techniques were applied to ICC cell lines to explore the influences of brusatol on ICC cells; this conclusion was further verified in animal models.Methods: The anti-cancer effects of the drug on the cell, protein, and RNA level were verified by cell functional experiments, WB blotting and transcriptome sequencing experiments, respectively. Finally, the experimental results were verified using subcutaneous tumor experiments in nude mice.Results: The consequences exhibited that the levels of epithelial markers of ICC cells increased after brusatol treatment, and the levels of interstitial indicators decreased, suppressing the epithelial-mesenchymal transition (EMT) process. Brusatol inhibited proliferation, induced apoptosis, and suppressed the migration and invasion abilities of Hucc-T1 and RBE oncocytes via activating PI3K/Akt pathway. It also suppressed the growth of Hucc-T1 xenografts in nude mice.Conclusion: Brusatol inhibits the proliferation and EMT process in ICC oncocytes by the PI3K/Akt pathway and promotes apoptosis in oncocytes.