Jinhua Ning, Nini Zhan, Zhanpan Wu, Yuzhe Li, Die Zhang, Yadian Shi, Yingxun Zhou, Chuan-Huizi Chen and Wenbin Jin
{"title":"通过调节 p21、γH2AX 和裂解 PARP,体外鉴定可诱导细胞周期停滞和细胞凋亡的潜在抗肿瘤坏死细胞药物 oridonin hybrids。","authors":"Jinhua Ning, Nini Zhan, Zhanpan Wu, Yuzhe Li, Die Zhang, Yadian Shi, Yingxun Zhou, Chuan-Huizi Chen and Wenbin Jin","doi":"10.1039/D4MD00580E","DOIUrl":null,"url":null,"abstract":"<p >TNBC has been recognized as the most highly aggressive breast cancer without chemotherapeutic drugs. A collection of oridonin hybrids consisting of conventional antitumor pharmacophores including nitrogen mustards and adamantane-1-carboxylic acid were synthesized by deletion or blockade of multiple hydroxyl groups and structural rearrangement. Compound <strong>11a</strong> showed the most promising anti-TNBC activity with nearly 15-fold more potent antiproliferative effects than oridonin against MDA-MB-231 and HCC1806. Moreover, <strong>11a</strong> significantly inhibited HCC1806, MDA-MB-231 and MDA-MB-468 cell proliferation by arresting cells at the G2/M phase in a dose-dependent manner. Furthermore, <strong>11a</strong> could trigger dose-dependently early and late apoptosis in those indicated cell lines. More importantly, <strong>11a</strong> could significantly increase p21, γH2AX and cleaved PARP accumulation in a dose-dependent manner. Furthermore, compound <strong>11a</strong> exhibited better stability than oridonin in a plasma assay. Taken together, all results demonstrated that <strong>11a</strong> may warrant further investigation as a promising anticancer drug candidate for the treatment of TNBC.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 11","pages":" 3674-3694"},"PeriodicalIF":4.1000,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"In vitro identification of oridonin hybrids as potential anti-TNBC agents inducing cell cycle arrest and apoptosis by regulation of p21, γH2AX and cleaved PARP†\",\"authors\":\"Jinhua Ning, Nini Zhan, Zhanpan Wu, Yuzhe Li, Die Zhang, Yadian Shi, Yingxun Zhou, Chuan-Huizi Chen and Wenbin Jin\",\"doi\":\"10.1039/D4MD00580E\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >TNBC has been recognized as the most highly aggressive breast cancer without chemotherapeutic drugs. A collection of oridonin hybrids consisting of conventional antitumor pharmacophores including nitrogen mustards and adamantane-1-carboxylic acid were synthesized by deletion or blockade of multiple hydroxyl groups and structural rearrangement. Compound <strong>11a</strong> showed the most promising anti-TNBC activity with nearly 15-fold more potent antiproliferative effects than oridonin against MDA-MB-231 and HCC1806. Moreover, <strong>11a</strong> significantly inhibited HCC1806, MDA-MB-231 and MDA-MB-468 cell proliferation by arresting cells at the G2/M phase in a dose-dependent manner. Furthermore, <strong>11a</strong> could trigger dose-dependently early and late apoptosis in those indicated cell lines. More importantly, <strong>11a</strong> could significantly increase p21, γH2AX and cleaved PARP accumulation in a dose-dependent manner. Furthermore, compound <strong>11a</strong> exhibited better stability than oridonin in a plasma assay. Taken together, all results demonstrated that <strong>11a</strong> may warrant further investigation as a promising anticancer drug candidate for the treatment of TNBC.</p>\",\"PeriodicalId\":21462,\"journal\":{\"name\":\"RSC medicinal chemistry\",\"volume\":\" 11\",\"pages\":\" 3674-3694\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-08-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"RSC medicinal chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2024/md/d4md00580e\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"RSC medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2024/md/d4md00580e","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
In vitro identification of oridonin hybrids as potential anti-TNBC agents inducing cell cycle arrest and apoptosis by regulation of p21, γH2AX and cleaved PARP†
TNBC has been recognized as the most highly aggressive breast cancer without chemotherapeutic drugs. A collection of oridonin hybrids consisting of conventional antitumor pharmacophores including nitrogen mustards and adamantane-1-carboxylic acid were synthesized by deletion or blockade of multiple hydroxyl groups and structural rearrangement. Compound 11a showed the most promising anti-TNBC activity with nearly 15-fold more potent antiproliferative effects than oridonin against MDA-MB-231 and HCC1806. Moreover, 11a significantly inhibited HCC1806, MDA-MB-231 and MDA-MB-468 cell proliferation by arresting cells at the G2/M phase in a dose-dependent manner. Furthermore, 11a could trigger dose-dependently early and late apoptosis in those indicated cell lines. More importantly, 11a could significantly increase p21, γH2AX and cleaved PARP accumulation in a dose-dependent manner. Furthermore, compound 11a exhibited better stability than oridonin in a plasma assay. Taken together, all results demonstrated that 11a may warrant further investigation as a promising anticancer drug candidate for the treatment of TNBC.