Background: Tyrosine kinase inhibitors (TKIs) inhibit receptor-mediated signals in cells. Axitinib is a TKI with high specificity for vascular endothelial growth factor receptors (VEGFRs). Aim: We determined whether axitinib could induce senescence in human cancer cells and be lysed by the senolytic drug ABT-263. Methods: Human lung and breast adenocarcinoma cell lines were used. These cells were cultured with axitinib or a multi-target TKI lenvatinib. The expression of β-galactosidase, VEGFRs, Ki-67, reactive oxygen species (ROS) of cancer cells, and their BrdU uptake were evaluated by flow cytometry. The mRNA expression of p21 and IL-8 was examined by quantitative PCR. The effects of TKIs on phosphorylation of Akt and Erk1/2, as downstream molecules of VEGFR signaling, were examined by immunoblot. The in vivo anti-cancer effect was examined using a xenograft mice model. Results: Axitinib, but not lenvatinib, induced cellular senescence (increased cell size and enhanced expression of β-galactosidase) in all adenocarcinoma cell lines. Axitinib-induced senescence was unrelated to the expression of VEGFRs on cancer cells. ROS were involved in axitinib-induced senescence. Axitinib-induced senescent lung adenocarcinoma A549 cells were drastically lysed by ABT-263. In A549-xenografted mice, combination therapy with axitinib and ABT-263 significantly suppressed tumor growth with the induction of apoptotic cancer cells.
背景：酪氨酸激酶抑制剂（TKIs）能够抑制细胞中受体介导的信号传导。阿昔替尼是一种对血管内皮生长因子受体（VEGFRs）具有高度特异性的TKI。目的：本研究旨在探讨阿昔替尼是否能诱导人类癌细胞衰老，并能否被衰老细胞清除药物ABT-263裂解。方法：采用人类肺腺癌和乳腺腺癌细胞系。这些细胞分别与阿昔替尼或多靶点TKI乐伐替尼共培养。通过流式细胞术评估癌细胞的β-半乳糖苷酶表达、VEGFRs表达、Ki-67表达、活性氧（ROS）水平及其BrdU摄取情况。采用定量PCR检测p21和IL-8的mRNA表达水平。通过免疫印迹法检测TKIs对VEGFR信号通路下游分子Akt和Erk1/2磷酸化的影响。利用异种移植小鼠模型评估体内抗癌效果。结果：在所有腺癌细胞系中，阿昔替尼（而非乐伐替尼）均能诱导细胞衰老（表现为细胞体积增大和β-半乳糖苷酶表达增强）。阿昔替尼诱导的衰老与癌细胞表面VEGFRs的表达无关。ROS参与了阿昔替尼诱导的衰老过程。ABT-263能显著裂解阿昔替尼诱导衰老的肺腺癌A549细胞。在A549异种移植小鼠模型中，阿昔替尼与ABT-263联合治疗通过诱导癌细胞凋亡，显著抑制了肿瘤生长。
Therapeutic Senolysis of Axitinib-Induced Senescent Human Lung Cancer Cells
肿瘤(癌症)患者之家