Simvastatin Enhanced Anti-tumor Effects of Bevacizumab against Lung Adenocarcinoma A549 Cells via Abating HIF-1α-Wnt/β-Catenin Signaling Pathway

Abstract

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 via 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 in vivo 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.

Screening of potential key ferroptosis-related genes in Chronic Obstructive Pulmonary Disease

“…Studies have shown that Simvastatin enhances the anti-tumor effects of bevacizumab against lung adenocarcinoma A549 Cells by abating the HIF-1α-Wnt/β-Catenin signaling pathway. 47 , 48 However, research on simvastatin targeting PPARG and KRAS for the treatment of COPD is relatively scarce. Research has shown that the antioxidant N-acetylcysteine (NAC) has been identified as a novel inhibitor of the hypoxic response pathway.…”

Nanomedicine for cancer targeted therapy with autophagy regulation

“…Furthermore, simvastatin's anticancer effects may also be associated with its inhibition of Shh signaling, increased levels of RhoA-GTP, increased levels of HIF-1a, and induction of p38 MAPK activation etc. (30)(31)(32).…”