Simvastatin Enhanced Anti-tumor Effects of Bevacizumab against Lung Adenocarcinoma A549 Cells <i>via</i> Abating HIF-1&#945;-Wnt/&#946;-Catenin Signaling Pathway

Author(s):

Xin Tu, Jian Zhang, Wei Yuan, Xia Wu, Zhi Xu and Cuo Qing*   Pages 2083 - 2094 ( 12 )

Abstract:

<p> Background: Bevacizumab increased hypoxia-inducible factor (HIF-1&#945;) expression attenuates its antitumor effect. Simvastatin can reduce the expression of HIF-1&#945; 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. </p> <p> Objective: To determine whether simvastatin could strengthen the anti-tumor activity of bevacizumab in lung adenocarcinoma. </p> <p> 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-1&#945; and &#946;-Catenin were determined <i>via</i> 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. </p> <p> 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-1&#945; and &#946;-Catenin than the control groups, however simvastatin group showed the opposite trend. Its combination with bevacizumab induced elevation of HIF-1&#945; and &#946;-catenin expressions. During <i>in vivo</i> experiments, simvastatin inhibited tumor growth, and in comparison, the inhibitory effects of its combination with bevacizumab were stronger. </p> <p> Conclusion: Based on our findings, simvastatin may affect the biological responses of bevacizumab on A549 cells by restraining the HIF-1&#945;-Wnt/&#946;-catenin signaling pathway, thus representing a novel and effective combination therapy that can be potentially applied in a clinical therapy for lung adenocarcinoma.</p>

Keywords:

Lung adenocarcinoma, simvastain, bevacizuma, HIF-1&#945;, &#946;-catenin, anti-tumor effects.

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