Article(id=1308840556168573066, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308840287129141340, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0648, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1749398400000, receivedDateStr=2025-06-09, revisedDate=1766073600000, revisedDateStr=2025-12-19, acceptedDate=null, acceptedDateStr=null, onlineDate=1789981505671, onlineDateStr=2026-09-21, pubDate=1775923200000, pubDateStr=2026-04-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789981505671, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789981505671, creator=13701087609, updateTime=1789981505671, updator=13701087609, issue=Issue{id=1308840287129141340, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='4', pageStart='1001', pageEnd='1434', issueExtLink='null', onlineDate='null', pubDate='1775923200000', pubDateStr='2026-04-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789981441528, creator='13701087609', updateTime=1789984228828, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308851977992368434, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308840287129141340, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308851977992368435, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308840287129141340, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1190, endPage=1198, ext={EN=ArticleExt(id=1308840557888237707, articleId=1308840556168573066, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Cryptotanshinone inhibits colorectal cancer cell proliferation by inducing ferroptosis via GPX4, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

This study aims to investigate the inhibitory effects of cryptotanshinone (CPT) on colorectal cancer (CRC) both in vitro and in vivo, and to explore its potential mechanism of action based on ferroptosis. CRC HCT116 and HCT8 cells were treated with different concentrations of CPT. Cell counting, colony formation assays, and Annexin V/PI staining revealed that CPT significantly inhibited CRC cell viability and proliferation and promoted apoptosis. A CRC patient-derived organoid (PDO) (in accordance with the regulations of the Nankai University Biomedical Ethics Committee approval number NKUIRB2025036) model was established, and cell counting, hematoxylin-eosin (HE) staining, and immunohistochemistry (IHC) detection of the tumor marker Ki67 confirmed that CPT suppressed PDO growth and malignant proliferation. A mouse xenograft tumor model was established (in compliance with the regulations of the Animal Ethics Committee of Tianjin University of Traditional Chinese Medicine, approval number: TCM-LAEC2025259K2011). Measurements of tumor volume and weight, HE staining, and Ki67 IHC demonstrated that CPT significantly inhibited tumor growth in vivo. Further studies found that a ferroptosis inhibitor could reverse the inhibitory effect of CPT on CRC cell proliferation, and CPT showed synergistic effects with ferroptosis inducers. Western blot and other detection results showed that CPT reduced the ratio of intracellular reduced glutathione (GSH) to oxidized glutathione (GSSG), and increased the levels of 4-hydroxynonenal (4-HNE) and the lipid peroxidation product malondialdehyde (MDA). Mechanistic studies indicated that CPT decreased glutathione peroxidase 4 (GPX4) mRNA levels and protein expression in a concentration-dependent manner. In conclusion, CPT can induce ferroptosis in CRC cells through GPX4, thereby inhibiting CRC cell proliferation and exerting anti-colorectal cancer effects.

, authors=Yi-chen KOU1, Xin-ru ZHAI2, Zhen-ting GUAN1, Huan-ran SUN2, Xiang-ling WANG1, Chang-liang SHAN2, *, Shuai ZHANG1, 3, *, authorsList=Yi-chen KOU, Xin-ru ZHAI, Zhen-ting GUAN, Huan-ran SUN, Xiang-ling WANG, Chang-liang SHAN, Shuai ZHANG, authorCompany=null, correspAuthors=Chang-liang SHAN, Shuai ZHANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1308840560010555547, articleId=1308840556168573066, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=隐丹参酮通过GPX4诱导铁死亡抑制结直肠癌细胞增殖, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

本研究旨在探讨隐丹参酮(cryptotanshinone, CPT) 在体内外对结直肠癌(colorectal cancer, CRC) 的抑制作用, 并基于铁死亡探讨其可能的作用机制。对结直肠癌HCT116和HCT8细胞给予不同浓度CPT处理, 通过细胞计数和克隆形成实验以及Annexin V/PI染色法发现CPT显著抑制CRC细胞活力和增殖能力, 促进细胞凋亡; 构建CRC类器官模型(patient-derived organoid, PDO, 遵循南开大学生物医学伦理委员会规定, 批件号: NKUIRB2025036), 通过细胞计数、苏木精-伊红(hematoxylin-eosin, HE) 染色和肿瘤标志物Ki67的免疫组织化学(immunohistochemistry, IHC) 检测证实CPT抑制PDO的生长和恶性增殖; 建立小鼠移植瘤模型(遵循天津中医药大学动物伦理委员会规定, 批准号: TCM-LAEC2025259K2011), 通过检测肿瘤体积与质量、HE染色和Ki67的IHC证实CPT显著抑制体内肿瘤生长。进一步研究发现, 铁死亡抑制剂可以逆转CPT对CRC细胞增殖的抑制作用并且CPT与铁死亡诱导剂具有协同增效的作用。Western blot等检测结果显示CPT降低细胞内还原型谷胱甘肽(reduced glutathione, GSH) 和氧化型谷胱甘肽(oxidized glutathione, GSSG) 的比值, 升高4-羟基壬烯醛(4-hydroxynonenal, 4-HNE) 含量与脂质过氧化物丙二醛(malondialdehyde, MDA) 水平。机制研究表明, CPT呈浓度依赖性地降低谷胱甘肽过氧化物酶4 (glutathione peroxidase 4, GPX4) mRNA水平及蛋白表达。综上所述, CPT可通过GPX4诱导CRC细胞铁死亡, 从而抑制CRC细胞增殖, 发挥抗结直肠癌的作用。

, authors=寇翼辰1, 翟心如2, 关振霆1, 孙焕然2, 王相玲1, 山长亮2, *, 张帅1, 3, *, authorsList=寇翼辰, 翟心如, 关振霆, 孙焕然, 王相玲, 山长亮, 张帅, authorCompany=null, correspAuthors=山长亮, 张帅, authorNote=

作者贡献:

山长亮和张帅负责课题总体设计; 寇翼辰、翟心如、关振霆、孙焕然负责完成实验的具体实施; 寇翼辰和王相玲负责实验数据分析、文章撰写; 山长亮和张帅对课题进行及论文撰写进行指导。

, correspAuthorsNote=
山长亮, E-mail:
张帅, E-mail:
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A: Representative images of CRC tumor-bearing model mice treated with the indicated doses of CPT; B: Tumor volume growth curves in mice treated with CPT; C: Representative images of excised tumors; D: Tumor weight at the end of the experiment. n = 5, x ± s. ****P < 0.000 1, figureFileSmall=fj2x3Urrp1NoGkoIoWmJBw==, figureFileBig=BsvhJGBRQk0nVepujg6++Q==, tableContent=null), ArticleFig(id=1308840568373997791, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840556168573066, language=EN, label=null, caption=null, figureFileSmall=HMJMPdt8SPZ1qBBAG9ulIA==, figureFileBig=JIsK+KokjPDCRW04UBmzfQ==, tableContent=null), ArticleFig(id=1308840568432718048, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840556168573066, language=CN, label=Fig.5, caption=The effect of CPT on ferroptosis of CRC cell. A, B: Ferroptosis inhibitor DFO rescues the suppression of CPT on cell growth in HCT116 (A) and HCT8 (B) cells; C: Colony formation assay of CPT and DFO in HCT8 cells; D-G: Cell counting and colony formation assay of CPT and ferroptosis inducer erastin in CRC cells HCT116 (D and E) and HCT8 (F and G). n = 3, x ± s. **P < 0.01, ***P < 0.001. DFO: Deferoxamine, figureFileSmall=HMJMPdt8SPZ1qBBAG9ulIA==, figureFileBig=JIsK+KokjPDCRW04UBmzfQ==, tableContent=null), ArticleFig(id=1308840568495632609, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840556168573066, language=EN, label=null, caption=null, figureFileSmall=ogPPSXAr2czMbZWGfuIF8A==, figureFileBig=G5wUB2Im0HIN9BjFuN6v6w==, tableContent=null), ArticleFig(id=1308840568558547170, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840556168573066, language=CN, label=Fig.6, caption=The effect of CPT on ferroptosis-related indicators in CRC cells. A, B: The polymer level of 4-HNE in HCT116 (A) and HCT8 (B) cells treated with the indicated doses of CPT; C, D: Statistical expression of MDA expression levels in HCT116 (C) and HCT8 (D) cells treated with the indicated doses of CPT; E: The level of LipROS in HCT116 cells under different concentrations of CPT; F, G: Statistical GSH level, GSSG level and GSH/GSSG ratio in CRC HCT116 (F) and HCT8 (G) cells. n = 3, x ± s. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.000 1. 4-HNE: 4-Hydroxynonenal; MDA: Malondialdehyde; GSH: Reduced glutathione; GSSG: Oxidized glutathione, figureFileSmall=ogPPSXAr2czMbZWGfuIF8A==, figureFileBig=G5wUB2Im0HIN9BjFuN6v6w==, tableContent=null), ArticleFig(id=1308840568667599075, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840556168573066, language=EN, label=null, caption=null, figureFileSmall=0BwuoVtiKjkpMeozaTIEVA==, figureFileBig=yMw+j6KZ6YGstq32p49MlQ==, tableContent=null), ArticleFig(id=1308840568730513636, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840556168573066, language=CN, label=Fig.7, caption=The mRNA and protein expression level of GPX4 in CRC cells. A, B: The mRNA expression level of GPX4 in HCT116 (A) and HCT8 (B) cells treated with different concentrations of CPT; C, D: The protein expression level of GPX4 in HCT116 (C) and HCT8 (D) cells treated with different concentrations of CPT. n = 3, x ± s. **P < 0.01, ***P < 0.001, ****P < 0.000 1. 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隐丹参酮通过GPX4诱导铁死亡抑制结直肠癌细胞增殖
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寇翼辰 1 , 翟心如 2 , 关振霆 1 , 孙焕然 2 , 王相玲 1 , 山长亮 2, * , 张帅 1, 3, *
药学学报 | 研究论文 2026,61(4): 1190-1198
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药学学报 |研究论文 2026 , 61 (4) : 1190 -1198
隐丹参酮通过GPX4诱导铁死亡抑制结直肠癌细胞增殖
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寇翼辰1, 翟心如2, 关振霆1, 孙焕然2, 王相玲1, 山长亮2, * , 张帅1, 3, *
作者信息
  • 1天津中医药大学中西医结合学院, 天津 301617
  • 2南开大学药学院, 天津 300350
  • 3天津中医药大学现代中药创制全国重点实验室, 天津 301617
通讯作者:
山长亮, E-mail:
张帅, E-mail:
作者简介:

作者贡献:

山长亮和张帅负责课题总体设计; 寇翼辰、翟心如、关振霆、孙焕然负责完成实验的具体实施; 寇翼辰和王相玲负责实验数据分析、文章撰写; 山长亮和张帅对课题进行及论文撰写进行指导。

Cryptotanshinone inhibits colorectal cancer cell proliferation by inducing ferroptosis via GPX4
Yi-chen KOU1, Xin-ru ZHAI2, Zhen-ting GUAN1, Huan-ran SUN2, Xiang-ling WANG1, Chang-liang SHAN2, * , Shuai ZHANG1, 3, *
Affiliations
  • 1School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
  • 2College of Pharmacy, Nankai University, Tianjin 300350, China
  • 3State Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
出版时间: 2026-04-12 doi: 10.16438/j.0513-4870.2025-0648
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本研究旨在探讨隐丹参酮(cryptotanshinone, CPT) 在体内外对结直肠癌(colorectal cancer, CRC) 的抑制作用, 并基于铁死亡探讨其可能的作用机制。对结直肠癌HCT116和HCT8细胞给予不同浓度CPT处理, 通过细胞计数和克隆形成实验以及Annexin V/PI染色法发现CPT显著抑制CRC细胞活力和增殖能力, 促进细胞凋亡; 构建CRC类器官模型(patient-derived organoid, PDO, 遵循南开大学生物医学伦理委员会规定, 批件号: NKUIRB2025036), 通过细胞计数、苏木精-伊红(hematoxylin-eosin, HE) 染色和肿瘤标志物Ki67的免疫组织化学(immunohistochemistry, IHC) 检测证实CPT抑制PDO的生长和恶性增殖; 建立小鼠移植瘤模型(遵循天津中医药大学动物伦理委员会规定, 批准号: TCM-LAEC2025259K2011), 通过检测肿瘤体积与质量、HE染色和Ki67的IHC证实CPT显著抑制体内肿瘤生长。进一步研究发现, 铁死亡抑制剂可以逆转CPT对CRC细胞增殖的抑制作用并且CPT与铁死亡诱导剂具有协同增效的作用。Western blot等检测结果显示CPT降低细胞内还原型谷胱甘肽(reduced glutathione, GSH) 和氧化型谷胱甘肽(oxidized glutathione, GSSG) 的比值, 升高4-羟基壬烯醛(4-hydroxynonenal, 4-HNE) 含量与脂质过氧化物丙二醛(malondialdehyde, MDA) 水平。机制研究表明, CPT呈浓度依赖性地降低谷胱甘肽过氧化物酶4 (glutathione peroxidase 4, GPX4) mRNA水平及蛋白表达。综上所述, CPT可通过GPX4诱导CRC细胞铁死亡, 从而抑制CRC细胞增殖, 发挥抗结直肠癌的作用。

结直肠癌  /  隐丹参酮  /  类器官  /  铁死亡  /  谷胱甘肽过氧化物酶4

This study aims to investigate the inhibitory effects of cryptotanshinone (CPT) on colorectal cancer (CRC) both in vitro and in vivo, and to explore its potential mechanism of action based on ferroptosis. CRC HCT116 and HCT8 cells were treated with different concentrations of CPT. Cell counting, colony formation assays, and Annexin V/PI staining revealed that CPT significantly inhibited CRC cell viability and proliferation and promoted apoptosis. A CRC patient-derived organoid (PDO) (in accordance with the regulations of the Nankai University Biomedical Ethics Committee approval number NKUIRB2025036) model was established, and cell counting, hematoxylin-eosin (HE) staining, and immunohistochemistry (IHC) detection of the tumor marker Ki67 confirmed that CPT suppressed PDO growth and malignant proliferation. A mouse xenograft tumor model was established (in compliance with the regulations of the Animal Ethics Committee of Tianjin University of Traditional Chinese Medicine, approval number: TCM-LAEC2025259K2011). Measurements of tumor volume and weight, HE staining, and Ki67 IHC demonstrated that CPT significantly inhibited tumor growth in vivo. Further studies found that a ferroptosis inhibitor could reverse the inhibitory effect of CPT on CRC cell proliferation, and CPT showed synergistic effects with ferroptosis inducers. Western blot and other detection results showed that CPT reduced the ratio of intracellular reduced glutathione (GSH) to oxidized glutathione (GSSG), and increased the levels of 4-hydroxynonenal (4-HNE) and the lipid peroxidation product malondialdehyde (MDA). Mechanistic studies indicated that CPT decreased glutathione peroxidase 4 (GPX4) mRNA levels and protein expression in a concentration-dependent manner. In conclusion, CPT can induce ferroptosis in CRC cells through GPX4, thereby inhibiting CRC cell proliferation and exerting anti-colorectal cancer effects.

colorectal cancer  /  cryptotanshinone  /  organoid  /  ferroptosis  /  glutathione peroxidase 4
寇翼辰, 翟心如, 关振霆, 孙焕然, 王相玲, 山长亮, 张帅. 隐丹参酮通过GPX4诱导铁死亡抑制结直肠癌细胞增殖. 药学学报, 2026 , 61 (4) : 1190 -1198 . DOI: 10.16438/j.0513-4870.2025-0648
Yi-chen KOU, Xin-ru ZHAI, Zhen-ting GUAN, Huan-ran SUN, Xiang-ling WANG, Chang-liang SHAN, Shuai ZHANG. Cryptotanshinone inhibits colorectal cancer cell proliferation by inducing ferroptosis via GPX4[J]. Acta Pharmaceutica Sinica, 2026 , 61 (4) : 1190 -1198 . DOI: 10.16438/j.0513-4870.2025-0648
结直肠癌(colorectal cancer, CRC) 是世界上最常见的消化道恶性肿瘤之一[1], 也是全球肿瘤死亡的第三大常见原因[2], 生活习惯和饮食结构的改变, 我国结肠癌的发病率呈逐年递增趋势, 近年来, 虽然在结肠癌的诊断和治疗方法上有明显提高, 但5年生存率仍不足60%[3]。传统治疗手段如手术、放化疗等有一定的治疗效果, 但肿瘤的复发、转移以及患者生存质量降低等问题使得寻找安全有效的防治肿瘤转移药物成为医学的一项迫切任务[4, 5]。结直肠癌的发病是多环节、多步骤的反复性过程, 在肿瘤的发生发展过程中, 细胞死亡常常发生在实体瘤的核心区域, 因此诱发肿瘤细胞死亡仍是肿瘤治疗的有效方法之一[6, 7]。
铁死亡(ferroptosis) 是近年来发现的一种新的调节性细胞死亡形式, 主要依赖铁介导的氧化损伤和细胞膜损伤, 通过外在或转运蛋白依赖性途径、内在或酶调节途径两种方式启动, 其中铁积累、自由基产生、脂肪酸供应和专用酶脂质过氧化的增加都可诱导铁死亡发生[8]。目前有研究表明, 铁死亡与肿瘤、神经系统疾病和血液疾病等的发生有关[9, 10]。肿瘤细胞整体代谢较活跃, 活性氧(reactive oxygen species, ROS) 负荷高, 对铁离子依赖高, 较普通细胞更容易受到铁影响, 更容易发生铁元素诱导下的死亡[11]。铁死亡是氧化应激诱导的细胞死亡代谢形式, 癌细胞利用额外的遗传或表观遗传改变来对抗这些代谢和氧化负荷[12]。结直肠癌作为拥有两种铁获取来源的恶性肿瘤, 包括循环中的铁的全身摄取, 以及肠腔铁的摄取, 更易受铁的影响, 因此靶向铁死亡可能成为治疗结直肠癌潜在的有效治疗方式[11]。
隐丹参酮(cryptotanshinone, CPT) 是一种从丹参提取得到的天然脂溶性二萜类化合物, 是丹参的活性有效物质之一。近年来对隐丹参酮的抗肿瘤作用研究较多, 如隐丹参酮通过阻滞癌细胞的生长周期和调控信号转导等方式来抑制癌细胞的增殖并诱导其凋亡等[13, 14]。本研究通过体外培养人结肠癌细胞和类器官模型及构建小鼠移植瘤模型, 探究隐丹参酮通过诱导铁死亡治疗结直肠癌的作用机制, 为寻找新的抑制结直肠癌细胞生长, 靶向结直肠癌细胞铁死亡的新型药物提供理论依据。
主要药品、试剂  隐丹参酮购自源叶公司(货号: S31670); erastin购自MedChemExpress公司(货号: Cat# HY-15763); 4-羟基壬烯醛(4-hydroxynonenal, 4-HNE) 抗体(货号: Cat# ab46545, RRID: AB_722490)、谷胱甘肽过氧化物酶4 (glutathione peroxidase 4, GPX4) 抗体(货号: 67763-1-lg)、β-actin抗体(货号: CL594-66009) 和Ki67抗体(货号: Cat# 27309-1-AP, RRID: AB_2756525) 购自Proteintech公司; 丙二醛(malondialdehyde, MDA) 试剂盒(货号: A003-2-2)、还原型谷胱甘肽(reduced glutathione, GSH)/氧化型谷胱甘肽(oxidized glutathione, GSSG) 试剂盒(货号: A061-1-2) 购自南京建成公司; 脂质过氧化检测试剂盒购自上海碧云天生物试剂公司(BODIPY 581/591 C11); BCA试剂盒(货号: B6169) 和DMSO (货号: D8371) 购自北京索莱宝科技有限公司; Annexin-V-APC/PI试剂盒购自西安维科图睿生物科技有限公司(货号: A5001-02P-M); 实时荧光定量PCR试剂盒(货号: 1141ES60) 和结晶紫染色液(货号: G1063) 购自苏州优逸兰迪生物科技有限公司; TRIzol reagent总RNA提取试剂购自康为试剂生物科技股份有限公司(货号: 15596018); 结直肠癌类器官培养基购自中科普瑞昇生物医药科技有限公司(货号: PRS-ICM-3D); 10%胎牛血清购自ExCell Bio公司(货号: DX-1001); 1640培养基购自Thermo Fisher Scientific公司(货号: 6124575); PBS缓冲液购自广州赛库生物技术有限公司(货号: CM2018); 甲醛固定液购自赛东南生物公司(货号: wsjc-5L)。
细胞培养  人结直肠癌细胞HCT116、HCT8、小鼠结肠癌细胞CT26培养于10%胎牛血清, 1%青霉素-链霉素的PRIM 1640培养基中, 置于37 ℃、5% CO2的培养箱中培养。
细胞生长曲线实验  收集待测HCT116和HCT8细胞, 以每孔1×104个细胞接种于24孔板, 每组3个复孔, 继续培养48 h后, 每24 h取3孔计数, 绘制细胞生长曲线, 进行结果分析。
细胞克隆形成实验  收集待测HCT116和HCT8细胞, 以每孔300个接种于12孔板, 每组3个复孔。继续培养14天, 去除培养基, PBS冲洗1次, 结晶紫染色20 min, 利用Bio-Rad ChemiRS凝胶成像系统成像, 采用Image J分析。计数每孔含50个细胞以上的细胞团数, 取3孔的平均值。
细胞凋亡实验  收集大约1×106个待测HCT116和HCT8细胞重悬于100 μL含有Annexin-V-APC/PI的缓冲液中。在室温避光孵育15 min后, 使用流式细胞仪分析。
结直肠癌类器官模型(patient-derived organoid, PDO) 培养和活力测定  将收集的结直肠癌手术切除肿瘤组织(遵循南开大学生物医学伦理委员会规定, 批件号: NKUIRB2025036) 剪碎成0.5~1 mm3的组织碎块, 消化制备单细胞悬液, 以每孔5×104个肿瘤细胞接种于含Matrigel胶的24孔板中, 结直肠癌类器官培养基继续培养, 每2天观察细胞状态和类器官形成数量, 待5~7天后可形成50~100 μm的类器官, 在类器官培养基中加入不同浓度的CPT, 处理5天后, 用CellTiter-Glo 3D reagent (G9683型, 美国Promega公司) 测定细胞活力, 并使用显微镜记录类器官形态变化。
小鼠荷瘤模型构建、分组和给药  实验动物雌性BALB/c小鼠6周龄24只, 体重16~18 g, 购自北京维通利华实验动物技术有限公司, 合格证号: SCXK (京) 2021-0006。将小鼠结肠癌细胞CT26皮下注射到BALB/c小鼠的左前肢, 细胞接种量为每只小鼠接种5×106个细胞。15只BALB/c小鼠随机分为3组(n = 5), 分别为模型组、CPT (20 mg·kg-1) 组和CPT (80 mg·kg-1) 组。模型组小鼠每日灌胃0.2 mL橄榄油, 其他各组小鼠均从CT26细胞注射次日起, 每日灌胃给予不同浓度的CPT橄榄油溶液, 连续21天。期间测量肿瘤体积。实验结束后, 测量肿瘤体积与重量。所有动物实验操作均经天津中医药大学动物伦理委员会批准(批准号: TCM-LAEC2025259K2011), 并严格遵循实验动物伦理规范以减少动物痛苦。
脂质过氧化物MDA水平和GSH以及GSSG含量检测  收集细胞并加入相应提取试剂研磨破碎, 离心后取上清, 根据说明书配置空白、标准、待测组反应体系, 加入样本并充分反应。在波长405和532 nm处读取吸光度A405和A532, 根据检测试剂盒的说明分别计算各组MDA、GSH和GSSG含量以及GSH/GSSG比值。
LipROS检测  细胞处理结束后去除培养液, 各组细胞与脂质活性氧(lipid reactive oxygen species, LipROS) 的荧光探针C11BODIPY 581/591 (2 μmol·L-1) 在室温、避光孵育30 min。流式细胞仪检测细胞LipROS的变化。
RT-qPCR收集细胞, 按照实时荧光定量PCR试剂盒说明书提取细胞总RNA, 将RNA逆转录合成cDNA后进行实时PCR检测, 结束后保存并下载扩增曲线、溶解曲线、Ct值并进行数据分析。GPX4和GAPDH的引物由上海生工合成。正反链引物序列如下: GPX4上游: 5'-GAGGCAAGACCGAAGTAAACTAC-3', 下游: 5'-CCGAACTGGTTACACGGGAA-3'; GAPDH上游: 5'-AGCCACATCGCTCAGACAC-3', 下游: 5'-GCCCAATACGACCAAATCC-3'。
Western blot  收集各组细胞, 使用RIPA裂解提取细胞中的总蛋白, 使用BCA试剂盒测定蛋白浓度。取等量蛋白样品上样, 进行SDS-PAGE电泳、转膜, 5%脱脂奶粉封闭。4 ℃条件下一抗孵育过夜, 次日在室温下孵育二抗1 h, 使用ECL方法显影。
HE染色  加100 µL 4%多聚甲醛固定液, 使用100 µL枪头轻柔地重悬类器官和基质胶, 将混合物转移至EP管中轻轻混合, 放在冰上孵育至少1 h。4 ℃、1 500 r·min-1离心5 min, 吸出固定液和基质胶。琼脂糖固定后进行石蜡包埋、脱水、切片。标本石蜡切片后进行HE染色, 切片脱蜡至水后苏木素溶液染细胞核, 伊红染细胞质, 染色完成后进行脱水, 使用中性树胶封片, 倒置显微镜进行观察。
免疫组织化学染色  石蜡切片经脱蜡水化后, 3%甲醇过氧化氢封闭30 min; 微波抗原修复; 血清封闭; 加入一抗4 ℃过夜; 次日加入二抗孵育60 min; ABC复合液作用60 min; DAB显色。使用中性树胶封片, 倒置显微镜进行观察。
统计学方法  以上实验至少各重复3次。使用GraphPad Prism 9.00软件完成实验数据的分析、整理与统计。两样本间比较采用t检验分析; 多组样本比较使用单因素方差分析(one way ANOVA), 从而进行显著性分析, 以平均值±标准差的形式展示实验结果。P < 0.05认为具有显著性差异。
不同浓度CPT (0、0.625、1.25、2.5、5、10、25和50 μmol·L-1) 作用于HCT116和HCT8细胞48 h后计数, 与对照组相比, 细胞存活率随CPT浓度增大逐渐降低, 其IC50分别为3.112 ± 0.459和2.623 ± 0.294 μmol·L-1 (图1A、B)。根据测定的IC50, 以空白组、1/2 IC50、IC50、2 IC50的剂量设置4个分组, 绘制HCT116和HCT8细胞的生长曲线以检测CPT对CRC细胞增殖能力的影响, 结果显示生长曲线均随着药物浓度的增加呈浓度依赖性降低(图1C、D)。克隆形成实验结果显示, CRC细胞克隆形成率随着给药浓度的增加而降低(图1E、F)。以上结果表明, CPT对CRC细胞的生长和增殖具有较强的抑制作用。
经过不同浓度的CPT处理48 h后流式细胞术检测CPT对CRC细胞凋亡的影响。与对照组相比, 随着CPT浓度升高, HCT116和HCT8细胞的凋亡率呈浓度依赖性升高(图2A、B)。
体外构建CRC PDO模型, 首先用0、5、15和30 μmol·L-1 4个不同浓度的CPT给药处理, 发现PDO细胞存活率随着CPT给药浓度的增加而降低。同时计算IC50为9.248 μmol·L-1 (图3A、B), 因此选择9.248 μmol·L-1为给药浓度分别设置CPT组和DMSO对照组, 并检测其形态学变化。HE染色结果显示, DMSO对照组呈现含中空内腔的特异性聚集形态, CPT组并未观察到该结构(图3C)。免疫组化学实验检测肿瘤标志物Ki67, 发现相较于DMSO组, CPT组中Ki67表达量显著降低(图3D)。以上实验表眀, CPT可以明显抑制结直肠癌类器官的生长。
为探究CPT在体内的抗结直肠癌作用, 构建了CRC移植瘤小鼠模型。结果显示, CPT可剂量依赖性地抑制小鼠肿瘤的生长(图4A、B), 表现为给药组的肿瘤体积与质量显著小于模型组(图4C、D)。表明其可有效抑制CRC细胞体内肿瘤生长。
为了确定铁死亡是否参与CPT对CRC细胞的活性抑制, 使用铁死亡抑制剂deferoxamine (DFO) 来进一步验证。将细胞分组为DMSO组、DFO组、CPT组、CPT+DFO组, 以期用DFO拮抗CPT诱导CRC细胞铁死亡。结果显示, DFO可以明显缓解CPT对HCT116和HCT8细胞的生长抑制作用(图5A~C)。将HCT116、HCT8细胞分为对照组、CPT组、erastin组、CPT和erastin联用组(CPT+erastin组) 4组。细胞计数和克隆形成实验结果显示, 与对照组相比, erastin组、CPT组和CPT+erastin组的细胞生长能力和克隆形成率较低, 结果表明CPT与铁死亡诱导剂具有显著的联合抑癌作用(图5D~G)。综上所述, CPT诱导发生铁死亡可能是其抑制CRC细胞生长增殖的机制之一。
铁死亡会引起细胞脂质过氧化水平(4-HNE)、细胞脂质过氧化产物MDA及细胞内GSH等相关指标变化。CPT处理CRC细胞后4-HNE加合物表达显著升高(图6A、B), MDA水平上升(图6C、D), LipROS水平上升(图6E), GSSG的含量上升, GSH的含量和GSH/GSSG比率下降(图6F、G)。研究结果表明, CPT诱导结直肠癌细胞铁死亡。
CPT处理HCT8、HCT116后收集细胞, RT-qPCR和Western blot检测铁死亡GPX4的mRNA和表达水平变化, 结果显示CPT可显著降低GPX4 mRNA和蛋白表达(图7)。GPX4是铁死亡的关键调控因子。结果表明, CPT通过抑制GPX4诱导铁死亡。
目前结直肠癌的临床治疗以手术治疗、化疗、靶向治疗、免疫治疗为主, 但仍存在一定不足。研究表明, 引发细胞死亡是杀死癌细胞的重要方法之一, 而肿瘤研究的关键问题之一是杀死癌细胞的同时, 尽量减少对正常细胞的伤害。铁死亡是由Stockwell团队[15]提出的、不同于其他形式的细胞死亡, 是铁诱发的非凋亡性细胞死亡。铁死亡的主要特征是铁异常积累, 并诱导ROS、MDA、Fe2+升高, GSH含量降低[16]。越来越多的研究表明, 可通过诱导肿瘤细胞发生铁死亡来抑制肿瘤进展[17, 18], 提示铁死亡可能是一种新的抗肿瘤治疗策略。目前认为, GPX4作为抑制铁死亡的关键抗氧化酶, 其功能失活是触发该程序性细胞死亡方式的中心环节。脂质过氧化反应是铁死亡的关键步骤[19], GPX4介导的细胞膜脂修复缺陷和ROS积累, 常导致细胞铁死亡[20]。Erastin可选择性杀死表达ST基因和RAS基因的肿瘤细胞, 被广泛应用为铁死亡的诱导剂, 其通过多种分子介导, 由细胞内脂质活性氧(LipROS) 以铁依赖性方式积累诱导的过氧化诱发铁死亡[21], 也常作为铁死亡诱导剂与药物联用, 验证药物协同增效的作用。研究表明, 临床用药可通过调控铁死亡治疗结直肠癌。铁死亡相关诱导剂erastin, 也可以协同化疗、免疫治疗、靶向治疗, 抑制结直肠肿瘤的进展[22]。
谷胱甘肽依赖性脂质氢过氧化物酶——GPX4可以有效诱导铁死亡和抑制耐药性肿瘤, GPX4通过将脂质氢过氧化物转化为无毒脂质醇, 防止铁死亡, 是防止铁死亡的主要酶及核心调节因子。通过使用谷胱甘肽作为辅助因子, 可解毒细胞脂质过氧化, 通过抑制GPX4诱导铁死亡, 引发癌细胞死亡[23-25]。
越来越多的证据表明天然产物具有治疗肿瘤的潜力, 且不良反应小[26]。隐丹参酮是中药丹参中的重要脂溶性成分[27], 可通过多种分子途径发挥抗癌作用[28-30]。本课题组前期利用分子对接和分子动力学模拟技术推测CPT可能与STAT3结合[31]。同时也有研究已证实, 在结直肠癌细胞中, STAT3作为转录因子调控GPX4的启动子活性及转录, 进而影响细胞铁死亡[32]。因此, 本课题组推测隐丹参酮靶向STAT3抑制GPX4的mRNA水平诱导铁死亡, 从而起到抗结直肠癌的作用。
综上所述, 本研究通过细胞、类器官和动物模型发现CPT可显著抑制结肠癌细胞生长、增殖和体内肿瘤生长, 机制上CPT可能通过抑制GPX4表达诱导CRC细胞铁死亡, 发挥治疗CRC的作用, 为CPT的药理作用及机制提供了实验依据。

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2026年第61卷第4期
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doi: 10.16438/j.0513-4870.2025-0648
  • 接收时间:2025-06-09
  • 首发时间:2026-09-21
  • 出版时间:2026-04-12
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  • 收稿日期:2025-06-09
  • 修回日期:2025-12-19
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    1天津中医药大学中西医结合学院, 天津 301617
    2南开大学药学院, 天津 300350
    3天津中医药大学现代中药创制全国重点实验室, 天津 301617

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2种不同金属材料的力学参数
科
Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)
属
Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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