摘要
目的:探究iRGD肽修饰共载姜黄素胡椒碱脂质体对非小细胞肺癌的抗肿瘤作用的分子机制。方法:基于网络药理学的方法预测姜黄素和胡椒碱治疗非小细胞肺癌(non-small cell lung cancer,NSCLC)的机制。制备iRGD肽修饰姜黄素胡椒碱脂质体并构建A549荷瘤裸鼠模型;HE染色法观察给药后的抗肿瘤药效情况;TUNEL染色法观察给药后肿瘤组织的细胞凋亡情况;Western blot法检测肿瘤组织cGAS、STING、P53、BAX、BCL-2蛋白表达;分子对接分析姜黄素/胡椒碱与STING/cGAS结合能力。结果:网络药理学结果分析表明,姜黄素和胡椒碱治疗非小细胞肺癌可能与BCL-2有关,姜黄素和胡椒碱可能通过细胞凋亡通路发挥抗肿瘤的作用。HE染色结果可见,给药后肿瘤组织可见不同程度的坏死区域,其中iRGD肽修饰的姜黄素胡椒碱脂质体组坏死区域较大;TUNEL染色结果可见,给药后肿瘤组织中均可见凋亡细胞,其中iRGD肽修饰的姜黄素胡椒碱脂质体组中凋亡细胞较多,且与模型对照组相比,各治疗组凋亡率均明显升高(P<0.05或P<0.01),肿瘤组织中cGAS、STING、P53、BAX/BCL-2表达均明显上调(P<0.05或P<0.01),iRGD肽修饰的姜黄素胡椒碱脂质体50 mg/kg组的cGAS、STING、P53、BAX/BCL-2蛋白表达上调,显著高于姜黄素胡椒碱脂质体50 mg/kg组和iRGD肽修饰的姜黄素脂质体50 mg/kg组(P<0.01);分子对接结果表明,姜黄素和胡椒碱与cGAS、STING结合能力较强。结论:iRGD肽修饰姜黄素胡椒碱脂质体能够显著提高姜黄素的抗肿瘤能力,姜黄素和胡椒碱能够与cGAS、STING结合,激活cGAS-STING信号通路,上调P53的表达,促进BAX/BCL-2比值上调,进而诱导非小细胞肺癌发生细胞凋亡;iRGD肽修饰的姜黄素胡椒碱脂质体的抗肿瘤效果优于无iRGD肽修饰的姜黄素胡椒碱脂质体,姜黄素与胡椒碱联用优于单用姜黄素的抗肿瘤效果。
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 pharmacology-based method was used to predict the treatment mechanism of CUR and PIP for NSCLC.iRGD-modified CURand PIP-loaded liposomes were prepared and an A549 tumor-bearing nude mouse model was constructed.Hematoxylin-eosin(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 administration.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 antitumor 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 treatment 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 expression of P53 and the BAX/BCL-2 ratio,thus inducing apoptosis in NSCLC.The anti-tumor effect of iRGD-modified CURand 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.
作者
陈佳源
黄训华
王英豪
黄美霞
王颖峥
CHEN Jiayuan;HUANG Xunhua;WANG Yinghao;HUANG Meixia;WANG Yingzheng(College of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350122)
出处
《中药药理与临床》
北大核心
2026年第1期44-51,共8页
Pharmacology and Clinics of Chinese Materia Medica
基金
福建省科技厅高校产学研合作项目(编号:2019N5010)
国家中医药管理局临床中药学高水平中医药重点学科建设项目(国中医药人教函[2023]85号)
福建省中医药重点学科建设项目(闽卫中医函[2024]363号)。
关键词
姜黄素
胡椒碱
非小细胞肺癌
脂质体
凋亡
Curcumin
Piperine
Non-small cell lung cancer
Liposomes
Apoptosis
