辛伐他汀增强贝伐单抗对肺腺癌 A549 细胞的抗肿瘤作用，减弱 HIF-1α-Wnt/β-连环蛋白信号通路。
Simvastatin Enhanced Anti-tumor Effects of Bevacizumab against Lung Adenocarcinoma A549 Cells Abating HIF-1α-Wnt/β-Catenin Signaling Pathway.
机构信息
Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital of Chengdu Medical College, Chengdu Pidu District People's Hospital, Chengdu, Sichuan, People's Republic of China.
Department of Gastroenterology, The Second People's Hospital of Yibin, Yibin, Sichuan, People's Republic of China.
出版信息
Anticancer Agents Med Chem. 2023;23(19):2083-2094. doi: 10.2174/1871520623666230816090914.
BACKGROUND
Bevacizumab increased hypoxia-inducible factor (HIF-1α) expression attenuates its antitumor effect. Simvastatin can reduce the expression of HIF-1α to exert a tumor-suppressive effect in many in vitro experiments. Therefore, this study aimed to determine whether simvastatin could strengthen the anti-tumor activity of bevacizumab in lung adenocarcinoma.
OBJECTIVE
To determine whether simvastatin could strengthen the anti-tumor activity of bevacizumab in lung adenocarcinoma.
METHODS
The changes in the biological behavior of A549 cells treated with different drugs were determined through colony forming assay, Cell Counting Assay-8 (CCK-8), transwell assay, wound healing assay, and flow cytometry. The expressions of pathway-related factors HIF-1α and β-Catenin were determined qRT-PCR and western blotting. The expressions of proliferation-related proteins, invasion-related proteins, and apoptosis-related proteins were detected by western blotting. In addition, a xenograft non-small cell lung cancer model in nude mice was used to explore in vivo tumor growth.
RESULTS
We found that simvastatin combined with bevacizumab synergistically suppressed the proliferation, migration, and invasion of A549 cells while promoting their apoptosis. As demonstrated by qRT-PCR and western blotting experiments, the bevacizumab group displayed a higher expression of pathway-related factors HIF-1α and β-Catenin than the control groups, however simvastatin group showed the opposite trend. Its combination with bevacizumab induced elevation of HIF-1α and β-catenin expressions. During experiments, simvastatin inhibited tumor growth, and in comparison, the inhibitory effects of its combination with bevacizumab were stronger.
CONCLUSION
Based on our findings, simvastatin may affect the biological responses of bevacizumab on A549 cells by restraining the HIF-1α-Wnt/β-catenin signaling pathway, thus representing a novel and effective combination therapy that can be potentially applied in a clinical therapy for lung adenocarcinoma.
背景
贝伐珠单抗增加缺氧诱导因子 (HIF-1α) 的表达，从而减弱其抗肿瘤作用。辛伐他汀可降低 HIF-1α 的表达，在许多体外实验中发挥肿瘤抑制作用。因此，本研究旨在确定辛伐他汀是否可增强贝伐珠单抗在肺腺癌中的抗肿瘤活性。
目的
确定辛伐他汀是否可增强贝伐珠单抗在肺腺癌中的抗肿瘤活性。
方法
通过集落形成实验、CCK-8 细胞计数实验、Transwell 实验、划痕愈合实验和流式细胞术，检测不同药物处理的 A549 细胞的生物学行为变化。采用 qRT-PCR 和 Western blot 检测通路相关因子 HIF-1α 和 β-catenin 的表达。Western blot 检测增殖相关蛋白、侵袭相关蛋白和凋亡相关蛋白的表达。此外，还使用裸鼠异种移植非小细胞肺癌模型来探索体内肿瘤生长情况。
结果
我们发现辛伐他汀联合贝伐珠单抗协同抑制 A549 细胞的增殖、迁移和侵袭，同时促进其凋亡。qRT-PCR 和 Western blot 实验结果表明，与对照组相比，贝伐珠单抗组的通路相关因子 HIF-1α 和 β-catenin 表达更高，而辛伐他汀组则呈现相反的趋势。两者联合使用后，HIF-1α 和 β-catenin 的表达增加。在实验过程中，辛伐他汀抑制肿瘤生长，与贝伐珠单抗联合使用时抑制效果更强。
结论
根据我们的研究结果，辛伐他汀可能通过抑制 HIF-1α-Wnt/β-catenin 信号通路来影响贝伐珠单抗对 A549 细胞的生物学反应，因此代表了一种新的有效的联合治疗方法，可能在肺腺癌的临床治疗中具有应用潜力。
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