Aumolertinib combined with anlotinib inhibits proliferation of non-small cell lung cancer cells by down-regulating the PI3K/AKT pathway

doi:10.12122/j.issn.1673-4254.2024.10.15

Abstract

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

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.

Figures/Tables 7

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

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.

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.

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.

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.

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.

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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