中国药理学通报2026，Vol.42Issue(2)：312-321,10.DOI:10.12360/CPB202506104
芍药内酯苷调控WWP1逆转卵巢癌荷瘤小鼠顺铂耐药
Study on albiflorin targeting WWP1 to reverse cisplatin resistance in ovarian cancer-bearing mice
摘要
Abstract
Aim To study the effect of albiflorin(AL)in reversing cisplatin resistance in ovarian can-cer-bearing mice and the underlying mechanism.Methods Nude mouse models of human ovarian can-cer SKOV3 cells and cisplatin-resistant SKOV3/DDP cells were established.The mice were divided into the control group(normal saline),cisplatin group(5.5 mg·kg-1),low-dose and high-dose AL groups(25,100 mg·kg-1),AL combined with cisplatin group(25 mg·kg-1 AL+5.5 mg·kg-1 cisplatin),WWP1 inhibitor MYCi975 group(50 mg·kg-1),and extrachromosomal circular DNA inhibitor hydroxyurea group(50 mg·kg-1).After blood collection at the end of administra-tion,the nude mice were sacrificed,the tumors were dissected,and the tumor inhibition rate was calcu-lated.RT-qPCR and Western blot were used to detect the expression of WWP1,PTEN and CDH1 genes and proteins in tumor tissues.ELISA was used to detect the expression of CDH1 factor in blood.Digital PCR was used to detect the expression of WWP1-eccDNA.Immunofluorescence was used to detect the expression of Ki67 in tumor tissues.ATAC-seq was used to assess chromatin accessibility in open genomic regions.Re-sults The results showed that compared with the cis-platin group of SKOV3 model nude mice,the tumor in-hibitory effect of cisplatin on SKOV3/DDP model nude mice was weakened,and the tumor inhibitory effect was enhanced after AL combined with cisplatin(P<0.05).Compared with the control group,after cispla-tin administration,the body weight of both SKOV3 model nude mice and SKOV3/DDP model nude mice decreased,the expression of WWP1-eccDNA,WWP1 mRNA and protein in tumor tissues increased,the ex-pression of CDH1 and PTEN mRNA and protein de-creased,and the level of CDH1 in blood decreased(P<0.05).After administration of AL alone or in combi-nation,the expression of WWP1-eccDNA,WWP1 mRNA and protein in tumor tissues decreased,the ex-pression of CDH1 and PTEN mRNA and protein in-creased,the level of CDH1 in the blood increased,and the expression of Ki67 in tumor tissues decreased(P<0.05).Accessibility of the WWP1 gene in open chromatin regions was reduced,whereas that of the PTEN gene was enhanced.There was no significant difference between the high-dose AL group and the MYCi975 group in regulating WWP1,PTEN,CDH1 mRNA and increasing the level of CDH1 in blood.The effect of increasing PTEN protein was stronger than that of the MYCi975 group.The inhibitory effects on WWP1 and CDH1 proteins were weaker than those of the MYCi975 group.There was no significant differ-ence between the inhibitory effect on WWP1-eccDNA and the hydroxyurea group.Conclusion AL can re-verse drug resistance of ovarian cancer in vivo,which may be related to the regulation of WWP1,PTEN,CDH1,and WWP1-eccDNA.关键词
卵巢癌/肿瘤多药耐药/芍药内酯苷/WWP1/CDH1/PTENKey words
ovarian cancer/multidrug resistance/al-biflorin/WWP1/CDH1/PTEN分类
医药卫生引用本文复制引用
郭晓娟,卢晨阳,杜瑞娟,卞华,郭克磊,张鹏,涂云飞,韩立..芍药内酯苷调控WWP1逆转卵巢癌荷瘤小鼠顺铂耐药[J].中国药理学通报,2026,42(2):312-321,10.基金项目
国家自然科学基金面上项目(No 82074076) （No 82074076）
河南省科技攻关项目(No 242102311268) （No 242102311268）
