iRGD肽修饰共载姜黄素胡椒碱脂质体调节cGAS/STING信号通路治疗非小细胞肺癌的机制研究OA

Objective:To explore the molecular mechanism of the inhibitory effect of iRGD-modified curcumin(CUR)-and piperine(PIP)-loaded liposomes on non-small cell lung cancer(NSCLC).Methods:A network pharma-cology-based method was used to predict the treatment mechanism of CUR and PIP for NSCLC.iRGD-modified CUR-and PIP-loaded liposomes were prepared and an A549 tumor-bearing nude mouse model was constructed.Hematoxylin-e-osin(HE)staining was employed to observe the anti-tumor efficacy after administration.Terminal-deoxynucleotidyl transferase-mediated nick-end labeling(TUNEL)was employed to observe the cell apoptosis of the tumor tissue after ad-ministration.Western blotting was employed to assess the protein levels of cyclic GMP-AMP synthase(cGAS),simulator of interferon genes(STING),P53,B-cell lymphoma-2(BCL-2),and BCL-2-associated X protein(BAX)in the tumor tissue.Molecular docking was performed to evaluate the binding affinity between CUR/PIP and STING/cGAS.Results:Network pharmacology analysis predicted that CUR and PIP might treat NSCLC via BCL-2 and they might exert anti-tumor effects via the apoptosis pathway.HE staining revealed areas with different degrees of necrosis in the tumor tissue after administration,and the necrosis area was larger in the iRGD-modified CUR-and PIP-loaded liposome group.TUNEL results showed that apoptotic cells were observed in the tumor tissue after administration,while more apoptotic cells in the iRGD-modified CUR-and PIP-loaded liposome group.Compared with the model control group,each treat-ment group showed increases in the apoptosis rate(P<0.05 or P<0.01)and expression of cGAS,STING,P53,and BAX/BCL-2 in the tumor tissue(P<0.05 or P<0.01).Moreover,the increasing trend of cGAS,STING,P53,and BAX/BCL-2 expression in the iRGD-modified CUR-and PIP-loaded liposome(50 mg/kg)group was higher than that in the CUR-and PIP-loaded liposome(50 mg/kg)group and the iRGD-modified CUR-loaded liposome(50 mg/kg)group(P<0.01).The molecular docking results showed that CUR and PIP had strong binding ability with cGAS and STING.Conclusion:iRGD-modified CUR-and PIP-loaded liposomes can significantly improve the anti-tumor effect of CUR,and CUR and PIP can bind to cGAS and STING to activate the cGAS-STING signaling pathway and up-regulate the expres-sion of P53 and the BAX/BCL-2 ratio,thus inducing apoptosis in NSCLC.The anti-tumor effect of iRGD-modified CUR-and PIP-loaded liposomes is better than that of CUR-and PIP liposomes without iRGD modification,and the combination of CUR and PIP has better anti-tumor effect than CUR alone.