Aidi Injection, a Traditional Chinese Medicine Extract, Reverses Gefitinib Resistance in Non-small Cell Lung Cancer Cells
Biswas, R; Yang, C-M; Lu, W; He, J; Chen, T; Tian, F; Li, Y
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Introduction Aidi injection is a traditional Chinese medicine containing multiple anti-tumour and immunomodulatory phytochemicals. While it synergistically enhances the efficacy of conventional chemotherapy in patients with non-small cell lung cancer (NSCLC), its effect on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) sensitivity in NSCLC remains unclear. This study aimed to investigate the effect and mechanisms of Aidi injection on the sensitivity of human NSCLC cell lines to gefitinib. Methods Effect of Aidi injection on gefitinib sensitivity was assessed by MTT, colony formation and apoptosis assays in three NSCLC cell lines (A549, HCC827 and H1975). The association between the expression of genes and the overall survival was analysed by accessing TCGA lung adenocarcinoma datasets. The effect of Aidi injection on multidrug resistance-associated protein 2 (MRP2, encoded by ABCC2 gene) function and gefitinib sensitivity was compared between parental HEK293 cell and HEK293 overexpressing MRP2 cells (HEK/MRP2). The principle components of Aidi injection were determined by LC-MS/MS and the interaction of Aidi components with MRP2 protein explored using molecular docking. Results Aidi injection enhanced gefitinib sensitivity (P < 0.05) and increased gefitinib-induced apoptosis rate (P < 0.05) in three NSCLC cell lines. Analysis of TCGA lung adenocarcinoma dataset showed that patients with a high expression of ABCC2 had significantly poorer survival (P = 0.007546). Aidi injection inhibited MRP2 activity in a concentration-dependant manner in HEK/MRP2 cells (P < 0.05). The combination of gefitinib with Aidi injection gave additive or weakly synergistic growth inhibition in HEK/MRP2 cells but exhibited antagonistic cytotoxicity in HEK293 cells. There were 11 main chemical components contained in Aidi injection, including astragalosides II and IV, cantharidin, etheutheroside E, ginsenosides Rb1, Rc, Rd, Re and Rg1, isofraxidin, and syringin. Docking studies showed strong affinity of Ginsenoside_Re towards MRP2. Conclusions Aidi injection may have the potential to be an adjuvant regimen to prevent and/or reverse common gefitinib resistance in NSCLC. The in silico and principle component analyses gives insight on ginsenoside_Re being a potential MRP2 inhibitor in Aidi injection.