• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

一种与5-氟尿嘧啶结合的新型钌配合物通过抑制Akt/mTOR信号传导来抑制结直肠癌干细胞。

A novel ruthenium complex with 5-fluorouracil suppresses colorectal cancer stem cells by inhibiting Akt/mTOR signaling.

作者信息

Silva Valdenizia R, Santos Luciano de S, de Castro Maria V L, Dias Rosane B, Valverde Ludmila de F, Rocha Clarissa A G, Soares Milena B P, Quadros Claudio A, Correa Rodrigo S, Batista Alzir A, Bezerra Daniel P

机构信息

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.

Department of Propedeutics, School of Dentistry of the Federal University of Bahia, Salvador, Bahia, 40110-909, Brazil.

出版信息

Cell Death Discov. 2023 Dec 16;9(1):460. doi: 10.1038/s41420-023-01759-6.

DOI:10.1038/s41420-023-01759-6
PMID:38104089
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10725484/
Abstract

[Ru(5-FU)(PPh)(bipy)]PF (Ru/5-FU) is a novel ruthenium complex with 5-fluorouracil with promising potential against colorectal cancer (CRC). In the present study, we investigated the molecular mechanism of Ru/5-FU action in HCT116 CRC cells. Ru/5-FU exhibited potent cytotoxicity on a panel of cancer cell lines and on primary cancer cells and induced apoptosis in HCT116 CRC cells. Ru/5-FU reduced AKT1 gene transcripts, as well as the expression of Akt1 and Akt (pS473) and downstream Akt proteins mTOR (pS2448), S6 (pS235/pS236), 4EBP1 (pT36/pT45), GSK-3β (pS9) and NF-κB p65 (pS529), but not Akt upstream proteins Hsp90 and PI3K p85/p55 (pT458/pT199), indicating an inhibitory action of Akt/mTOR signaling. Ru/5-FU increased LC3B expression and reduced p62/SQSTM1 levels, indicating autophagy induction. Curiously, the autophagy inhibitors 3-methyladenine and chloroquine increased Ru/5-FU-induced cell death, indicating an induction of cytoprotective autophagy by this compound. Ru/5-FU also reduced clonogenic survival, as well as the percentage of CD133+ cells and colonosphere formation, indicating that Ru/5-FU can suppress stem cells in HCT116 cells. Ru/5-FU inhibited cell migration and invasion in wound healing assays and Transwell cell invasion assays, along with a reduction in vimentin expression and an increase in E-cadherin levels, indicating that Ru/5-FU can interfere with epithelial-mesenchymal transition. Ru/5-FU also inhibited in vivo HCT116 cell development and experimental lung metastases in mouse xenograft models. Altogether, these results indicate that Ru/5-FU is an anti-CRC chemotherapy drug candidate with the ability to suppress stemness in CRC cells by inhibiting Akt/mTOR signaling.

摘要

[Ru(5-氟尿嘧啶)(三苯基膦)(联吡啶)]六氟磷酸根（Ru/5-氟尿嘧啶）是一种新型的钌配合物，与5-氟尿嘧啶结合，对结直肠癌（CRC）具有潜在的治疗潜力。在本研究中，我们探究了Ru/5-氟尿嘧啶在HCT116结直肠癌细胞中的作用分子机制。Ru/5-氟尿嘧啶对一组癌细胞系和原代癌细胞表现出强大的细胞毒性，并诱导HCT116结直肠癌细胞凋亡。Ru/5-氟尿嘧啶降低了AKT1基因转录本，以及Akt1和Akt（pS473）的表达以及下游Akt蛋白mTOR（pS2448）、S6（pS235/pS236）、4EBP1（pT36/pT45）、GSK-3β（pS9）和NF-κB p65（pS529）的表达，但不影响Akt上游蛋白Hsp90和PI3K p85/p55（pT458/pT199），表明其对Akt/mTOR信号通路具有抑制作用。Ru/5-氟尿嘧啶增加了LC3B的表达并降低了p62/SQSTM1水平，表明其诱导了自噬。奇怪的是，自噬抑制剂3-甲基腺嘌呤和氯喹增加了Ru/5-氟尿嘧啶诱导的细胞死亡，表明该化合物诱导了细胞保护性自噬。Ru/5-氟尿嘧啶还降低了克隆形成存活率，以及CD133+细胞的百分比和结肠球形成，表明Ru/5-氟尿嘧啶可以抑制HCT116细胞中的干细胞。在伤口愈合试验和Transwell细胞侵袭试验中，Ru/5-氟尿嘧啶抑制了细胞迁移和侵袭，同时波形蛋白表达降低，E-钙黏蛋白水平升高，表明Ru/5-氟尿嘧啶可以干扰上皮-间质转化。Ru/5-氟尿嘧啶还在小鼠异种移植模型中抑制了体内HCT116细胞的生长和实验性肺转移。总之，这些结果表明Ru/5-氟尿嘧啶是一种抗结直肠癌化疗药物候选物，具有通过抑制Akt/mTOR信号通路来抑制结直肠癌细胞干性的能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/f4124ba27233/41420_2023_1759_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/27ccf8b44e6f/41420_2023_1759_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/c265e74814ba/41420_2023_1759_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/a5f1653890d4/41420_2023_1759_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/cbb6230bd8ed/41420_2023_1759_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/7ba8c717783e/41420_2023_1759_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/8a9b2326f9ca/41420_2023_1759_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/c1a3a1ced320/41420_2023_1759_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/f4124ba27233/41420_2023_1759_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/27ccf8b44e6f/41420_2023_1759_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/c265e74814ba/41420_2023_1759_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/a5f1653890d4/41420_2023_1759_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/cbb6230bd8ed/41420_2023_1759_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/7ba8c717783e/41420_2023_1759_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/8a9b2326f9ca/41420_2023_1759_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/c1a3a1ced320/41420_2023_1759_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0e/10725484/f4124ba27233/41420_2023_1759_Fig8_HTML.jpg

相似文献

1
A novel ruthenium complex with 5-fluorouracil suppresses colorectal cancer stem cells by inhibiting Akt/mTOR signaling.一种与5-氟尿嘧啶结合的新型钌配合物通过抑制Akt/mTOR信号传导来抑制结直肠癌干细胞。
Cell Death Discov. 2023 Dec 16;9(1):460. doi: 10.1038/s41420-023-01759-6.
2
New ruthenium-xanthoxylin complex eliminates colorectal cancer stem cells by targeting the heat shock protein 90 chaperone.新型钌-桑辛素复合物通过靶向热休克蛋白 90 伴侣消除结直肠肿瘤干细胞。
Cell Death Dis. 2023 Dec 15;14(12):832. doi: 10.1038/s41419-023-06330-w.
3
Ruthenium complex containing 1,3-thiazolidine-2-thione inhibits hepatic cancer stem cells by suppressing Akt/mTOR signalling and leading to apoptotic and autophagic cell death.含 1,3-噻唑烷-2-硫酮的钌配合物通过抑制 Akt/mTOR 信号通路诱导肝癌干细胞凋亡和自噬死亡。
Biomed Pharmacother. 2024 Aug;177:117059. doi: 10.1016/j.biopha.2024.117059. Epub 2024 Jul 1.
4
[Hydroxysafflor yellow A inhibits proliferation, migration, and chemoresistance of colorectal cancer cells through Akt/mTOR-autophagy pathway].[羟基红花黄色素A通过Akt/mTOR-自噬途径抑制结肠癌细胞的增殖、迁移和化疗耐药性]
Zhongguo Zhong Yao Za Zhi. 2023 Jan;48(2):517-524. doi: 10.19540/j.cnki.cjcmm.20221014.703.
5
Resveratrol Chemosensitizes TNF-β-Induced Survival of 5-FU-Treated Colorectal Cancer Cells.白藜芦醇增敏 TNF-β 诱导的 5-FU 治疗的结直肠癌细胞的存活。
Nutrients. 2018 Jul 12;10(7):888. doi: 10.3390/nu10070888.
6
KIFC3 Promotes Proliferation, Migration, and Invasion in Colorectal Cancer PI3K/AKT/mTOR Signaling Pathway.驱动蛋白家族成员C3（KIFC3）通过PI3K/AKT/mTOR信号通路促进结直肠癌的增殖、迁移和侵袭。
Front Genet. 2022 Jun 22;13:848926. doi: 10.3389/fgene.2022.848926. eCollection 2022.
7
Atractylenolide I inhibits colorectal cancer cell proliferation by affecting metabolism and stemness via AKT/mTOR signaling.苍术内酯 I 通过影响 AKT/mTOR 信号通路来影响代谢和干性从而抑制结直肠癌细胞增殖。
Phytomedicine. 2020 Mar;68:153191. doi: 10.1016/j.phymed.2020.153191. Epub 2020 Feb 14.
8
Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling.钌（II）-胸腺嘧啶配合物通过 JNK/p38/ERK1/2 介导的 p53 非依赖性信号通路引起人结肠癌细胞 HCT116 的 DNA 损伤和凋亡性细胞死亡。
Sci Rep. 2019 Jul 31;9(1):11094. doi: 10.1038/s41598-019-47539-0.
9
Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice.姜黄素通过损害 AMPK/ULK1 依赖性自噬、AKT 活性和增强结肠癌细胞中的细胞凋亡，与 5-氟尿嘧啶协同作用，并抑制异种移植小鼠肿瘤生长。
J Exp Clin Cancer Res. 2017 Dec 22;36(1):190. doi: 10.1186/s13046-017-0661-7.
10
Extract of Thunb. enhances the inhibitory effect of 5-fluorouracil on gastric cancer cells through the AKT-mTOR pathway.雷公藤提取物通过 AKT-mTOR 通路增强 5-氟尿嘧啶对胃癌细胞的抑制作用。
World J Gastroenterol. 2019 Apr 21;25(15):1854-1864. doi: 10.3748/wjg.v25.i15.1854.

引用本文的文献

1
Metal-based molecules in the treatment of cancer: From bench to bedside.用于癌症治疗的金属基分子：从实验室到临床应用
Oncol Res. 2025 Mar 19;33(4):759-779. doi: 10.32604/or.2024.057019. eCollection 2025.
2
Ru(II)-based complexes containing 2-thiouracil derivatives suppress liver cancer stem cells by targeting NF-κB and Akt/mTOR signaling.含2-硫尿嘧啶衍生物的钌（II）配合物通过靶向NF-κB和Akt/mTOR信号通路抑制肝癌干细胞。
Cell Death Discov. 2024 Jun 3;10(1):270. doi: 10.1038/s41420-024-02036-w.
3
Cancer Stem Cells from Definition to Detection and Targeted Drugs.

本文引用的文献

1
Unlocking the potential of iridium and ruthenium arene complexes as anti-tumor and anti-metastasis chemotherapeutic agents.挖掘铱和钌芳烃配合物作为抗肿瘤和抗转移化疗药物的潜力。
J Inorg Biochem. 2023 Jan;238:112057. doi: 10.1016/j.jinorgbio.2022.112057. Epub 2022 Nov 2.
2
In Vitro and In Vivo Biological Activity of Ruthenium 1,10-Phenanthroline-5,6-dione Arene Complexes.钌 1,10-菲咯啉-5,6-二酮芳烃配合物的体外和体内生物学活性。
Int J Mol Sci. 2022 Nov 6;23(21):13594. doi: 10.3390/ijms232113594.
3
Molecular Design, Spectroscopic, DFT, Pharmacological, and Molecular Docking Studies of Novel Ruthenium(III)-Schiff Base Complex: An Inhibitor of Progression in HepG2 Cells.
从定义到检测与靶向药物的癌症干细胞
Int J Mol Sci. 2024 Mar 31;25(7):3903. doi: 10.3390/ijms25073903.
新型钌(III)-席夫碱配合物的分子设计、光谱、DFT、药理学和分子对接研究：一种抑制 HepG2 细胞进展的抑制剂。
Int J Environ Res Public Health. 2022 Oct 20;19(20):13624. doi: 10.3390/ijerph192013624.
4
New ruthenium complexes containing salicylic acid and derivatives induce triple-negative tumor cell death via the intrinsic apoptotic pathway.新型钌配合物包含水杨酸及其衍生物，通过内在凋亡途径诱导三阴性肿瘤细胞死亡。
Eur J Med Chem. 2022 Dec 5;243:114772. doi: 10.1016/j.ejmech.2022.114772. Epub 2022 Sep 16.
5
Mechanisms on chemotherapy resistance of colorectal cancer stem cells and research progress of reverse transformation: A mini-review.结直肠癌干细胞化疗耐药机制及逆转研究进展：综述
Front Med (Lausanne). 2022 Sep 12;9:995882. doi: 10.3389/fmed.2022.995882. eCollection 2022.
6
A Photoactivated Sorafenib-Ruthenium(II) Prodrug for Resistant Hepatocellular Carcinoma Therapy through Ferroptosis and Purine Metabolism Disruption.一种通过铁死亡和嘌呤代谢紊乱来治疗耐药性肝细胞癌的光激活索拉非尼-钌（II）前药。
J Med Chem. 2022 Oct 13;65(19):13041-13051. doi: 10.1021/acs.jmedchem.2c00880. Epub 2022 Sep 22.
7
Ruthenium(II)-Cyclopentadienyl-Derived Complexes as New Emerging Anti-Colorectal Cancer Drugs.钌（II）-环戊二烯基衍生物配合物作为新型抗结直肠癌药物
Pharmaceutics. 2022 Jun 17;14(6):1293. doi: 10.3390/pharmaceutics14061293.
8
Characteristics of the cancer stem cell niche and therapeutic strategies.肿瘤干细胞生态位的特征和治疗策略。
Stem Cell Res Ther. 2022 Jun 3;13(1):233. doi: 10.1186/s13287-022-02904-1.
9
Cyclometalated Ru(II)-isoquinoline complexes overcome cisplatin resistance of A549/DDP cells by downregulation of Nrf2 via Akt/GSK-3β/Fyn pathway.环金属化 Ru(II)-异喹啉配合物通过 Akt/GSK-3β/Fyn 通路下调 Nrf2 来克服 A549/DDP 细胞的顺铂耐药性。
Bioorg Chem. 2022 Feb;119:105516. doi: 10.1016/j.bioorg.2021.105516. Epub 2021 Nov 25.
10
Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells.靶向信号通路以根除结直肠肿瘤干细胞的新兴药物。
Cancer Commun (Lond). 2021 Dec;41(12):1275-1313. doi: 10.1002/cac2.12235. Epub 2021 Nov 17.