姜黄素纳米前药通过抑制CDKs和特异性下调PLK1诱导结直肠癌多相细胞周期阻滞

Q1 Engineering Smart Materials in Medicine Pub Date : 2023-01-01 DOI:10.1016/j.smaim.2023.06.001
Dong Xu , Xingzhi Feng , Yuxin Wan , Lanlan Yang , Qianling Gao , Zihuan Yang , Chang Du
{"title":"姜黄素纳米前药通过抑制CDKs和特异性下调PLK1诱导结直肠癌多相细胞周期阻滞","authors":"Dong Xu ,&nbsp;Xingzhi Feng ,&nbsp;Yuxin Wan ,&nbsp;Lanlan Yang ,&nbsp;Qianling Gao ,&nbsp;Zihuan Yang ,&nbsp;Chang Du","doi":"10.1016/j.smaim.2023.06.001","DOIUrl":null,"url":null,"abstract":"<div><p>Aberrant activation of cell cycle proteins leads to tumor progression in most cancer types. While 5-fluorouracil (5-Fu)-based chemotherapy remains the first-line treatment strategy for colorectal cancer (CRC), more than 40% of patients with advanced CRC do not benefit from the regimen. Herein, a chemically modified curcumin (mCur) was developed to explore its curative effect on CRC and reveal its potential role in cell cycle regulation. Amphiphilic mCur could self-assemble into positively charged nano-micelles, hence facilitating high cellular uptake and anticancer activity. Multi-phase cell cycle arrest, induced by both mCur and Cur, was first observed in HCT 116 ​cells. This phenomenon was mainly attributed to the Cur/mCur mediated downregulation of cyclin-dependent kinases (CDKs) and their direct interactions. Moreover, mCur and Cur treatments generated distinct phenotypic signatures. In particular, mCur induced distinct dynamic fluctuations in cell cycle and a relatively higher proportion of cells in the G2/M phase than Cur, and specifically triggered the impaired expression of polo-like kinase 1 (PLK1). An <em>in vivo</em> evaluation using a CRC patient-derived tumor xenograft (PDX) model indicated that mCur exhibited better antitumor effects via more significant downregulation of PLK1 in PLK1<sup>high</sup> PDX, with no obvious systemic toxicity. Collectively, our study revealed a unique multi-phase cell cycle arrest effect of Cur-based antitumor agents and highlighted the potential of mCur as a PLK1-targeted inhibitor for CRC therapy.</p></div>","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"4 ","pages":"Pages 648-660"},"PeriodicalIF":0.0000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Curcumin nano-prodrug induces multi-phase cell cycle arrest in colorectal cancer through suppression of CDKs and specific down-regulation of PLK1\",\"authors\":\"Dong Xu ,&nbsp;Xingzhi Feng ,&nbsp;Yuxin Wan ,&nbsp;Lanlan Yang ,&nbsp;Qianling Gao ,&nbsp;Zihuan Yang ,&nbsp;Chang Du\",\"doi\":\"10.1016/j.smaim.2023.06.001\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Aberrant activation of cell cycle proteins leads to tumor progression in most cancer types. While 5-fluorouracil (5-Fu)-based chemotherapy remains the first-line treatment strategy for colorectal cancer (CRC), more than 40% of patients with advanced CRC do not benefit from the regimen. Herein, a chemically modified curcumin (mCur) was developed to explore its curative effect on CRC and reveal its potential role in cell cycle regulation. Amphiphilic mCur could self-assemble into positively charged nano-micelles, hence facilitating high cellular uptake and anticancer activity. Multi-phase cell cycle arrest, induced by both mCur and Cur, was first observed in HCT 116 ​cells. This phenomenon was mainly attributed to the Cur/mCur mediated downregulation of cyclin-dependent kinases (CDKs) and their direct interactions. Moreover, mCur and Cur treatments generated distinct phenotypic signatures. In particular, mCur induced distinct dynamic fluctuations in cell cycle and a relatively higher proportion of cells in the G2/M phase than Cur, and specifically triggered the impaired expression of polo-like kinase 1 (PLK1). An <em>in vivo</em> evaluation using a CRC patient-derived tumor xenograft (PDX) model indicated that mCur exhibited better antitumor effects via more significant downregulation of PLK1 in PLK1<sup>high</sup> PDX, with no obvious systemic toxicity. Collectively, our study revealed a unique multi-phase cell cycle arrest effect of Cur-based antitumor agents and highlighted the potential of mCur as a PLK1-targeted inhibitor for CRC therapy.</p></div>\",\"PeriodicalId\":22019,\"journal\":{\"name\":\"Smart Materials in Medicine\",\"volume\":\"4 \",\"pages\":\"Pages 648-660\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Smart Materials in Medicine\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2590183423000182\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Engineering\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Smart Materials in Medicine","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2590183423000182","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Engineering","Score":null,"Total":0}
引用次数: 1

摘要

细胞周期蛋白的异常激活导致大多数癌症类型的肿瘤进展。虽然以5-氟尿嘧啶(5-Fu)为基础的化疗仍然是癌症(CRC)的一线治疗策略,但超过40%的晚期CRC患者没有从该方案中获益。本文开发了一种化学修饰的姜黄素(mCur),以探索其对CRC的疗效,并揭示其在细胞周期调控中的潜在作用。两亲性mCur可以自组装成带正电的纳米胶束,从而促进细胞的高摄取和抗癌活性。mCur和Cur诱导的多相细胞周期阻滞首次在HCT 116中观察到​细胞。这种现象主要归因于Cur/mCur介导的细胞周期蛋白依赖性激酶(CDKs)的下调及其直接相互作用。此外,mCur和Cur处理产生了不同的表型特征。特别是,mCur诱导了细胞周期的明显动态波动,G2/M期的细胞比例相对高于Cur,并特别触发了polo-like激酶1(PLK1)的表达受损。使用CRC患者来源的肿瘤异种移植物(PDX)模型进行的体内评估表明,mCur通过在PLK1高PDX中更显著地下调PLK1而表现出更好的抗肿瘤作用,没有明显的全身毒性。总之,我们的研究揭示了基于Cur的抗肿瘤药物独特的多期细胞周期阻滞作用,并强调了mCur作为PLK1靶向抑制剂用于CRC治疗的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Curcumin nano-prodrug induces multi-phase cell cycle arrest in colorectal cancer through suppression of CDKs and specific down-regulation of PLK1

Aberrant activation of cell cycle proteins leads to tumor progression in most cancer types. While 5-fluorouracil (5-Fu)-based chemotherapy remains the first-line treatment strategy for colorectal cancer (CRC), more than 40% of patients with advanced CRC do not benefit from the regimen. Herein, a chemically modified curcumin (mCur) was developed to explore its curative effect on CRC and reveal its potential role in cell cycle regulation. Amphiphilic mCur could self-assemble into positively charged nano-micelles, hence facilitating high cellular uptake and anticancer activity. Multi-phase cell cycle arrest, induced by both mCur and Cur, was first observed in HCT 116 ​cells. This phenomenon was mainly attributed to the Cur/mCur mediated downregulation of cyclin-dependent kinases (CDKs) and their direct interactions. Moreover, mCur and Cur treatments generated distinct phenotypic signatures. In particular, mCur induced distinct dynamic fluctuations in cell cycle and a relatively higher proportion of cells in the G2/M phase than Cur, and specifically triggered the impaired expression of polo-like kinase 1 (PLK1). An in vivo evaluation using a CRC patient-derived tumor xenograft (PDX) model indicated that mCur exhibited better antitumor effects via more significant downregulation of PLK1 in PLK1high PDX, with no obvious systemic toxicity. Collectively, our study revealed a unique multi-phase cell cycle arrest effect of Cur-based antitumor agents and highlighted the potential of mCur as a PLK1-targeted inhibitor for CRC therapy.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Smart Materials in Medicine
Smart Materials in Medicine Engineering-Biomedical Engineering
CiteScore
14.00
自引率
0.00%
发文量
41
审稿时长
48 days
期刊最新文献
Bioactive matters based on natural product for cardiovascular diseases Current situation and challenges of polyhydroxyalkanoates-derived nanocarriers for cancer therapy Nanobody-as versatile tool emerging in autoimmune diseases Bioactive MXene hydrogel promotes structural and functional regeneration of skeletal muscle through improving autophagy and muscle innervation Progress of smart material in the repair of intervertebral disc degeneration
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1