Combination of Apatinib and Salidroside Inhibits the Progression of Non-Small Cell Lung Cancer through MAPK/ERK/VEGF Signaling Axis

Abstract

Background: Lung cancer is the leading cause of cancer-related deaths, where non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. The potential of apatinib, a small-molecule anti-angiogenic drug, and salidroside, the Chinese herbal extract, as anti-tumor agents has been recognized. Therefore, this study aims to investigate the synergistic effects of apatinib and salidroside on NSCLC and provide insights into this combination to evaluate their combined potential in treating NSCLC. Methods: 3-(4,5-dimethylthiazol)-2,5-diphenyl-tetrazolium bromide (MTT) assay was employed to determine the inhibitory effects of different concentrations of apatinib, salidroside and their combination on NSCLC cell proliferation. The levels of reactive oxygen species (ROS) in NSCLC cells were assessed in treated cells. Furthermore, flow cytometry, wound healing assay, and tube formation assay were used to determine the apoptosis rate, migration ability, and angiogenesis of cells, respectively. Additionally, western blot analysis was utilized to evaluate the levels of apoptosis-related proteins and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)/vascular endothelial growth factor (VEGF) axis-related proteins. Results: Compared to using either apatinib or salidroside for treatment alone, apatinib in combination with salidroside (Sal) significantly inhibited NSCLC cell proliferation, migration, and tube formation (p < 0.01). Meanwhile, this combination ((apatinib) Apa+Sal) induced ROS production and promoted apoptosis by up-regulating Bcl-2 associated X (Bax) expression and down-regulating B cell lymphoma-2 (Bcl-2) expression (p < 0.01). Western blot analysis revealed a substantial increase in the phosphor (p)-p38 expression, and decreased p-ERK, VEGF, and VEGF receptor (VEGFR) levels in the combined treated group compared to the single treatment group (p < 0.05). Combined treatment coupled with MAPK/ERK inhibitor (SB203580) or activator (anisomycin) significantly enhanced or decreased the inhibitory effect of apatinib and salidroside on human umbilical vein endothelial cells (HUVEC) tube formation, respectively. Conclusion: Apatinib in combination with salidroside exerts a synergistic anticancer effect in NSCLC by down-regulating the MAPK/ERK/VEGF signaling axis, which suggests the potential of this combined therapy in treating NSCLC.