阿美替尼联合安罗替尼通过下调PI3K/AKT通路抑制非小细胞肺癌细胞的增殖

doi:10.12122/j.issn.1673-4254.2024.10.15

摘要/Abstract

摘要：

目的探究阿美替尼联合安罗替尼抑制非小细胞肺癌的作用。方法 CCK-8法、集落克隆法和流式细胞术检测不同浓度阿美替尼和安罗替尼对PC-9细胞和HCC827细胞增殖、细胞存活和细胞凋亡的影响；SynergyFinder模型评价阿美替尼与安罗替尼的协同作用；Transwell小室实验检测阿美替尼联合安罗替尼对PC-9细胞和HCC827细胞侵袭及迁移的作用；Western blotting实验检测阿美替尼联合安罗替尼对PC-9细胞和HCC827细胞凋亡和侵袭迁移相关蛋白Bax、Bcl-2、E-Cadherin、Vimentin、MMP2和MMP9及PI3K-Akt通路关键蛋白表达的影响。结果阿美替尼作用于PC-9细胞的IC₅₀为1.701 μmol/L，安罗替尼作用于PC-9细胞的IC₅₀=4.979 μmol/L，协同得分（ZIP）为19.112；阿美替尼对HCC827细胞IC₅₀=2.961 μmol/L，安罗替尼对HCC827细胞IC₅₀=7.934 μmol/L，协同得分（ZIP）为12.325，阿美替尼联合安罗替尼能够显著抑制PC-9细胞和HCC827细胞增殖（P<0.05）。相比于单药组，集落克隆结果表明阿美替尼联合安罗替尼能够显著抑制PC-9细胞和HCC827细胞存活（P<0.01）；流式细胞术结果表明，阿美替尼联合安罗替尼能够促进PC-9细胞和HCC827细胞发生凋亡（P<0.05）；Transwell实验结果表明，阿美替尼联合安罗替尼能够显著抑制PC-9细胞和HCC827细胞的侵袭迁移能力（P<0.01）；Western blotting实验结果表明，阿美替尼联合安罗替尼能够显著促进PC-9细胞和HCC827细胞中E-Cadherin和Bax蛋白的表达，抑制Bcl-2、Vimentin、MMP2和MMP9蛋白的表达（P<0.01），同时显著降低了PI3K-Akt通路中关键蛋白PI3K、Akt的磷酸化蛋白水平（P<0.01）。结论阿美替尼联合安罗替尼通过下调PI3K-Akt通路抑制NSCLC肿瘤细胞，这种联合治疗方式可能成为临床上治疗 NSCLC患者的一种潜在治疗策略。

关键词: 非小细胞肺癌, 阿美替尼, 安罗替尼, 凋亡, 侵袭迁移, PI3K-Akt

Abstract:

Objective To investigate the inhibitory effect of aumolertinib combined with anlotinib on proliferation of non-small cell lung cancer (NSCLC) cells. Methods CCK-8 assay, colony formation assay, and flow cytometry were used to assess the effect of different concentrations of aumolertinib or anlotinib on proliferation, survival, and apoptosis of PC-9 and HCC827 cells, and their synergistic effect was evaluated using the SynergyFinder model. In PC-9 and HCC827 cells treated with aumolertinib combined with anlotinib, the changes in cell invasion and migration abilities were assessed with Transwell assay, and the expressions of apoptosis- and invasion/migration-related proteins (Bax, Bcl-2, E-cadherin, vimentin, MMP2, and MMP9) and the key PI3K-Akt pathway proteins were detected using Western blotting. Results In PC-9 cells, the IC50 of aumolertinib and anlotinib was 1.701 μmol/L and 4.979 μmol/L, respectively, with a synergy score (ZIP) of 19.112; in HCC827 cells, their IC50 was 2.961 μmol/L and 7.934 μmol/L, respectively, with a ZIP of 12.325. Compared with aumolertinib and anlotinib used alone, their combined treatment more strongly inhibited the proliferation and survival, enhanced apoptosis and suppressed invasion and migration abilities of PC-9 and HCC827 cells. Western blotting showed that in both PC-9 and HCC827 cells, the combined treatment significantly upregulated the expressions of E-cadherin and Bax proteins, downregulated the expressions of Bcl-2, vimentin, MMP2, and MMP9 proteins, and reduced phosphorylation levels of PI3K and Akt. Conclusion Aumolertinib combined with anlotinib can effectively inhibit NSCLC cell proliferation by downregulating the PI3K-Akt pathway, suggesting a potentially new option for NSCLC treatment.

Key words: non-small cell lung cancer, aumolertinib, anlotinib, apoptosis, invasion and migration, PI3K-Akt pathway

杨玉梅, 刘雪柔, 刘伟, 周星琦, 张振, 胡妍, 刘培培, 李娴, 刘浩, 李姗姗. 阿美替尼联合安罗替尼通过下调PI3K/AKT通路抑制非小细胞肺癌细胞的增殖[J]. 南方医科大学学报, 2024, 44(10): 1965-1975.

Yumei YANG, Xuerou LIU, Wei LIU, Xingqi ZHOU, Zhen ZHANG, Yan HU, Peipei LIU, Xian LI, Hao LIU, Shanshan LI. Aumolertinib combined with anlotinib inhibits proliferation of non-small cell lung cancer cells by down-regulating the PI3K/AKT pathway[J]. Journal of Southern Medical University, 2024, 44(10): 1965-1975.

图/表 7

表1 抗体信息

Tab.1 Antibodies used in this study

Antibody name	Company	Dilution rate
Anti-beta actin	Affinity biosciences	1:5000
Anti-E-cadherin	Proteintech	1:5000
Anti-Vimentin	Proteintech	1:1000
Anti-Bax	Proteintech	1:2000
Anti-Bcl-2	Proteintech	1:2000
Anti-MMP2	Affinity biosciences	1:1000
Anti-MMP9	Affinity biosciences	1:1000
Anti-PI3K	Proteintech	1:1000
Anti-AKT	Proteintech	1:5000
Anti-p-PI3K	Cell signaling technology	1:1000
Anti-p-AKT	Cell signaling technology	1:2000

图1 Aum和An抑制NSCLC细胞增殖与存活

Fig.1 Aumolertinib (Aum), anlotinib (An) and their combination significantly inhibits NSCLC cell proliferation and survival. A: Effect of Aum on PC-9 cells. B: Inhibitory effect of An in PC-9 cells. C: Inhibitory effect of Aum in HCC827 cells. D. Inhibitory effect of An in HCC827 cells. E: Colony cloning. F, G: Statistics of colony formation in HCC827 cells, **P<0.01, ***P<0.001 vs 0 μmol/L Control, ##P<0.01, ###P<0.001.

图2 Aum联合An对PC-9及HCC827细胞的抑制具有协同作用

Fig.2 Aumolertinib combined with anlotinib synergistically inhibit viability of PC-9 and HCC827 cells. A, B: CCK-8 assay. C, D: Synergy scores of Aumolertinib combined with anlotinib in PC-9 cells (ZIP<0 indicates an antagonistic effect of the two drugs, 0<ZIP<10 indicates that the two drugs have antagonistic effects, and 0<ZIP<10 indicates that the two drugs have antagonistic effect, and 0<ZIP<10 indicates that the two drugs have synergy effect). ZIP<10 indicates that the two drugs have additive effect, and 10<ZIP indicates that the two drugs have synergistic effect. E,F: Synergy scores of aumolertinib combined with anlotinib in HCC827 cells. *P<0.05, **P<0.01, ***P<0.001.

图 3 Aum联合An明显促进PC-9细胞及HCC827细胞的凋亡

Fig.3 Aumolertinib combined with anlotinib promotes apoptosis of PC-9 cells and HCC827 cells. A: Flow cytometric analysis of apoptosis in different treatment groups. B, C: Apoptosis rates in the 4 groups. D: Apoptosis-related proteins analyzed using protein immunoblotting; E,F: Quantitative analysis of apoptotic protein expression levels. *P<0.05, **P<0.01, ***P<0.001 vs control; #P<0.05, ##P<0.01, ###P<0.001.

图4 Aum联合An抑制PC-9细胞及HCC827细胞的侵袭和迁移

Fig.4 Aumolertinib combined with anlotinib significantly inhibits invasion and migration of PC-9 cells and HCC827 cells. A,D: Transwell assay for assessing cell invasion and migration in different groups (crystalline violet staining, original magnification: ×200). G, I: Scratch assay for assessing migration ability of the cells in different groups (×200). H,J: Quantitative analysis of PC-9 and HCC827 cell migration. *P<0.05, **P<0.01, ***P<0.001 vs control; ###P<0.001.

图 5 Aum联合An调控PC-9细胞及HCC827细胞的侵袭迁移相关蛋白的表达

Fig.5 Western blotting for the expression of E-cadherin, vimentin, MMP2 and MMP9 in PC-9 cells or HCC827 cells (A) and their relative of protein expression levels (B, C). *P<0.05, **P<0.05,***P<0.001 vs control; #P<0.05,##P<0.01, ###P<0.001.

图6 Aum联合An通过阻断PI3K及Akt的磷酸化抑制PC-9细胞及HCC827细胞的侵袭和迁移

Fig.6 Aumolertinib combined with anlotinib inhibits invasion and migration of PC-9 cells and HCC827 cells by blocking phosphorylation of PI3K and Akt. A: Protein immunoblotting of PI3K-Akt pathway related proteins. B, C: Quantitative analysis of expression levels of PI3K-Akt pathway-related proteins. *P<0.05,**P<0.01 vs control,##P<0.01.

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