Ginkgolic Acid Enhances the Sensitivity of Liver Cancer Cells to Sorafenib via Up-Regulating CFL2

Abstract

Background: Ginkgolic acid (GA) impedes the invasion of cancer cells, and reverses the drug resistance of carboplatin-resistant cell lines. This study was conducted to explore the influence of GA on the sensitivity of liver cancer cells to sorafenib (SOR) and the relevant mechanism. Methods: Genes aberrantly expressed in GA-treated liver cancer cells and SOR-resistant liver cancer cells were analyzed by GEO2R, and cofilin 2 (CFL2) level in liver cancer cells was analyzed using the StarBase. Liver cancer cells were transfected with small interfering RNA targeting CFL2 (siCFL2). Subsequently, the cells were subjected to treatments with GA and SOR alone or together. Assessment of the viability, proliferation, and apoptosis of the treated cells was performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5‐ethynyl‐2′‐deoxyuridine (EdU) fluorescent staining, and flow cytometry assays, respectively. Quantification of proliferating cell nuclear antigen (PCNA), B-cell lymphoma 2 (Bcl-2), BCL2 associated X protein (Bax), Cleaved-caspase 3, and CFL2 in cell samples was achieved through quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Results: GA diminished cell viability and enhanced the effect of SOR on repressing the viability and proliferation, accelerating apoptosis, decreasing PCNA and Bcl-2 levels, and increasing Bax and Cleaved-caspase 3 levels in liver cancer cells. Low expression of CFL2 was observed in liver cancer cells, however, SOR elevated its level, and GA further enhanced this increment. Silencing CFL2 offset the aforementioned roles of GA in SOR-treated liver cancer cells. Conclusions: GA has the potential to enhance the sensitivity of liver cancer cells to SOR by increasing CFL2 level.