伊布替尼通过靶向 EGFR/AKT/mTOR 信号通路对胰腺癌细胞放射敏感性的影响。
The effect of ibrutinib on radiosensitivity in pancreatic cancer cells by targeting EGFR/AKT/mTOR signaling pathway.
机构信息
Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China; The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310006, China.
出版信息
Biomed Pharmacother. 2020 Aug;128:110133. doi: 10.1016/j.biopha.2020.110133. Epub 2020 May 22.
Radiotherapy is an effective treatment for pancreatic cancer. However, radio-resistance often resulted in poor prognostic. Ibrutinib is an orally small molecule drug in B cell malignancies. Here, we investigated for the first time the effect of ibrutinib on radio-sensitivity of human pancreatic cancer cells in vitro and the potential mechanism involved in it. Human BXPC3 and Capan2 cell lines were treated with ibrutinib, and cell viability was conducted with CCK-8 assay. Cell clone formation was observed after treated with ibrutinib and (or) radiation by clone formation assay. The cell cycle and cell apoptosis were measured by flow cytometry. Protein levels was analyzed by western blot. The results revealed that ibrutinib inhibited the proliferation of pancreatic cancer cells. Ibrutinib enhanced the effect of radiation with a sensitization enhancement ratio (SER) of 1.34, 1.68 in BXPC3 and Capan2 cells respectively. Ibrutinib combined with radiation induced G2/M arrest and cell apoptosis. Further investigations revealed that ibrutinib decreased the phosphorylation of EGFR, then reversed the upregulation of p-AKT and downstream genes by radiation. In conclusion, these results suggested that ibrutinib might be an excellent radiosensitizer in pancreatic cancer.
放射疗法是治疗胰腺癌的有效方法。然而，放射抗性常常导致预后不良。依鲁替尼是一种用于 B 细胞恶性肿瘤的口服小分子药物。在这里，我们首次研究了依鲁替尼对体外人胰腺癌细胞放射敏感性的影响及其潜在机制。用 CCK-8 法检测依鲁替尼处理后细胞活力，用克隆形成实验观察依鲁替尼和（或）辐射处理后细胞克隆形成。用流式细胞术检测细胞周期和细胞凋亡。用 Western blot 分析蛋白水平。结果表明，依鲁替尼抑制了胰腺癌细胞的增殖。依鲁替尼增强了辐射的作用，在 BXPC3 和 Capan2 细胞中的增敏比（SER）分别为 1.34 和 1.68。依鲁替尼联合辐射诱导 G2/M 期阻滞和细胞凋亡。进一步研究表明，依鲁替尼降低了 EGFR 的磷酸化，从而逆转了辐射引起的 p-AKT 及其下游基因的上调。总之，这些结果表明，依鲁替尼可能是胰腺癌的一种优秀的放射增敏剂。
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