ABSTRACT
BACKGROUND: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is a limited factor in the treatment of non-small-cell lung cancer (NSCLC) patients. Therefore, ongoing studies are trying to identify EGFR-TKIs-resistant mechanisms and to discover novel therapeutic strategies and targets for NSCLC treatment.METHODS: In the present study, the possibility of overcoming intrinsic gefitinib-resistance was examined by regulating the expression of AXL. A natural product-derived antitumor agent, yuanhuadine (YD) was employed to modulate the expression of AXL in the cells.RESULTS: Treatment with YD effectively downregulated AXL expression in AXL-overexpressed gefitinib-resistant H1299 cells. The combination of gefitinib and YD exhibited a synergistic grwoth-inhibitory activity in H1299 cells by downregulation of AXL expression.CONCLUSIONS: Based on these findings, AXL was found to be a promising therapeutic target to overcome the intrinsic resistance to gefitinib in NSCLC. Furthermore, YD is able to effectively regulate the expression of AXL and thus it may be applicable as a potential lead compound for the treatment of gefitinib-resistant NSCLC.
Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung , Down-Regulation , Drug Resistance , Lung Neoplasms , Protein-Tyrosine Kinases , ErbB ReceptorsABSTRACT
Objective To explore the expression and clinical significance of soluble Axl and Tyro3 receptor tyrosine kinase in systemic lupus erythematosus (SLE).Methods Sandwich enzyme linked immunosorbent assay (ELISA) was used to detect sAxlTK and sTyro3TK in the serum of 140 SLE patients,150 disease controls and 100 healthy controls (HC).The relationships between the serum levels of sAxlTK/sTyro3TK and clinical manifestations,laboratory parameters,disease activity were analyzed in SLE patients.Analysis of variance,Dunnett's t-test,chi-square test and spearman's test were used for statistical analysis.Results The concentrations of sAxlTK [(56±18) ng/ml] and sTyro3TK [(3.9±1.6) ng/ml] were both elevated in serum of SLE patients,which were significantly higher than disease controls [sAxlTK:(41±17) ng/ml;sTyro3TK:(2.6± 1.2) ng/ml] and healthy controls [sAxlTK:(37±10) ng/ml;sTyro3TK:(2.1±0.7) ng/ml].The SLE sAxlTK levels were negatively correlated with lymphocyte count (r=-0.266,P=0.002),hemoglobin (r=-0.480,P＜0.01),platelet count (r=-0.374,P＜0.01),albumin (r=-0.465,P＜0.01),estimated glomerular filtration rate (eGFR,r=-0.230,P=0.006),complement C3 (r=-0.399,P＜0.01) and complement C4 (r=-0.374,P＜0.01).However,the levels of sAxlTK in SLE patients were positively correlated with D-dimer (r=0.371,P＜0.01),creatinine (r=0.278,P＜0.01),24-hour urinary protein quantification (r=0.383,P＜0.01),erythrocyte sedimentation rate (r=0.422,P＜0.01),titre of anti-nuclear antibodies (r=0.271,P=0.002),anti-dsDNA antibody (r=0.299,P＜0.01),anti-nucleosome antibody (r=0.263,P=0.013) and anti-cardiolipin antibody (r=0.309,P＜0.01).In addition,the levels of serum sAxlTK in SLE patients showed positive correlation with the scores of SLEDAI (r=0.307,P＜0.01).Comparisons of sAxlTK levels between patients with high and low disease activity demonstrated a higher level of sAxlTK in the former [(64±17) ng/ml vs (52±16) ng/ml;t=-3.939,P＜0.01].Conclusion The levels of sAxlTK and sTyro3TK are elevated in the serum of SLE patients.The concentration of sAxlTK is correlated with autoantibodies production,hematological and renal involvement in SLE,which may be a serolgical marker for disease activity.