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Article(id=1308455574711066825, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308455410751525737, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0058, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1736956800000, receivedDateStr=2025-01-16, revisedDate=1743091200000, revisedDateStr=2025-03-28, acceptedDate=null, acceptedDateStr=null, onlineDate=1789889718940, onlineDateStr=2026-09-20, pubDate=1754928000000, pubDateStr=2025-08-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789889718940, onlineIssueDateStr=2026-09-20, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789889718940, creator=13701087609, updateTime=1789889718940, updator=13701087609, issue=Issue{id=1308455410751525737, tenantId=1146029695717560320, journalId=1189982191388893191, year='2025', volume='60', issue='8', pageStart='2375', pageEnd='2648', issueExtLink='null', onlineDate='null', pubDate='1754928000000', pubDateStr='2025-08-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789889679849, creator='13701087609', updateTime=1789893542748, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308471612978786380, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308455410751525737, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308471612978786381, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308455410751525737, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2528, endPage=2534, ext={EN=ArticleExt(id=1308455575222771914, articleId=1308455574711066825, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=The inhibition of biological behavior of gastric cancer cells by penfluridol through HSP90/Akt/MDM2/p53 signaling pathway, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

This study investigated the antitumor activity and molecular mechanisms of penfluridol (PF), an antipsychotic drug, in gastric cancer treatment. In vitro assays including CCK-8, colony formation, wound healing, Transwell migration, Hoechst 33342 staining, and flow cytometry demonstrated that penfluridol significantly inhibited proliferation and migration of SGC-7901 and HGC-27 gastric cancer cells in a concentration-dependent manner, while inducing apoptosis. Transcriptomic profiling combined with molecular docking revealed stable binding conformations between penfluridol and heat shock protein 90 (HSP90) or mouse double minute 2 (MDM2). Western blot analysis further confirmed that penfluridol suppressed the HSP90/protein kinase B/MDM2/tumor protein p53 (HSP90/Akt/MDM2/p53) pathway, characterized by decreased HSP90 expression and concomitant upregulation of p53 protein. These findings collectively indicate that penfluridol exerts multifaceted antitumor effects by targeting key oncogenic pathways, providing experimental evidence for repurposing this antipsychotic agent as a potential therapeutic strategy against gastric cancer.

, authors=Pei-li WANG1, 2, Qi-feng CHEN1, 2, Yi-xuan HUO2, Jia-rui WANG5, Rong HE2, Li-he JIANG1, 2, 3, 4, *, authorsList=Pei-li WANG, Qi-feng CHEN, Yi-xuan HUO, Jia-rui WANG, Rong HE, Li-he JIANG, authorCompany=null, correspAuthors=Li-he JIANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2025 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=1308455577139568853, articleId=1308455574711066825, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=五氟利多通过HSP90/Akt/MDM2/p53信号通路抑制胃癌细胞生物学行为的研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

本研究探讨了抗精神病药物五氟利多(penfluridol, PF) 在胃癌治疗中的抗肿瘤活性及其作用机制。通过CCK-8法、集落形成实验、划痕愈合实验、Transwell迁移实验、Hoechst 33342染色和流式细胞术等系列检测发现, 五氟利多可显著抑制SGC-7901和HGC-27胃癌细胞的增殖与迁移能力, 并呈现浓度依赖性诱导细胞凋亡的特征。为进一步揭示其作用机制, 结合转录组学分析与分子对接技术发现, 五氟利多能与热休克蛋白90 (heat shock protein 90, HSP90) 和鼠双微体2 (MDM2 proto-oncogene, MDM2) 蛋白形成稳定结合构象。Western blot实验证实五氟利多抑制了热休克蛋白90/蛋白激酶B/鼠双微体2/肿瘤蛋白p53信号通路, 其中HSP90表达水平下降伴随p53蛋白显著上调。研究结果表明, 五氟利多通过多种机制抑制胃癌细胞恶性生物学行为, 其调控网络涉及关键肿瘤信号通路, 为五氟利多作为潜在的胃癌治疗药物提供了实验依据。

, authors=王珮郦1, 2, 陈奇峰1, 2, 霍艺萱2, 王家瑞5, 贺蓉2, 蒋利和1, 2, 3, 4, *, authorsList=王珮郦, 陈奇峰, 霍艺萱, 王家瑞, 贺蓉, 蒋利和, authorCompany=null, correspAuthors=蒋利和, authorNote=

作者贡献:

王珮郦、陈奇峰共同承担实验研究与数据分析的工作; 王珮郦完成论文撰写与初步修订; 陈奇峰、霍艺萱分析转录组学测序数据; 王家瑞、贺蓉负责文献检索与综述; 蒋利和全程指导课题研究、提供经费支持, 并对论文进行审阅与关键性修订。

, correspAuthorsNote=
蒋利和, E-mail:
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affiliation=null, department=null, xref=1, 2, 3, 4, *, address=1Medical School of Guangxi University, Nanning 530004, China
2Basic Medical College of Youjiang Medical University for Nationalities, Baise 533000, China
3Guangxi Key Laboratory for Pharmaceutical Molecular Discovery and Druggability Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China
4Guangxi Colleges and Universities Key Laboratory of Human Development and Disease Research (Guangxi Medical University), Nanning 530021, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499179664670940, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455574711066825, authorId=1308499179517870294, language=CN, stringName=蒋利和, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, 2, 3, 4, *, address=1广西大学医学院, 广西 南宁 530004
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A, B: Inhibitory effects of PF on cell proliferation (CCK-8 assay) in SGC-7901 (A) and HGC-27 (B); C, D: Suppression of colony formation by PF in SGC-7901 (C) and HGC-27 (D). n = 3, $ \stackrel{-}{x} $ ± s. *P < 0.05, **P < 0.01, ***P < 0.001 vs control. PF: Penfluridol, figureFileSmall=l1zYVFX6v7yHoprx6fdXKg==, figureFileBig=r2zWKmccq60hS6lfjg9lKg==, tableContent=null), ArticleFig(id=1308499181531136235, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455574711066825, language=EN, label=null, caption=null, figureFileSmall=X9MEfcpgPBc4MHtUCh5jeQ==, figureFileBig=4U1lqjWyCibCwyKGhd8CWg==, tableContent=null), ArticleFig(id=1308499181615022316, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455574711066825, language=CN, label=Fig.2, caption=PF inhibits migration and epithelial-mesenchymal transition (EMT) in gastric cancer cells. A, C: Suppression of wound healing by PF in SGC-7901 (A) and HGC-27 (C); B, D: Inhibition of migration by PF in SGC-7901 (B) and HGC-27 (D); E, F: Regulation of EMT-related proteins by PF in SGC-7901 (E) and HGC-27 (F). n = 3, $ \stackrel{-}{x} $ ± s. *P < 0.05, **P < 0.01, ***P < 0.001 vs control, figureFileSmall=X9MEfcpgPBc4MHtUCh5jeQ==, figureFileBig=4U1lqjWyCibCwyKGhd8CWg==, tableContent=null), ArticleFig(id=1308499181682131181, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455574711066825, language=EN, label=null, caption=null, figureFileSmall=4jimDKys5oloo8uTgu2iig==, figureFileBig=qsRE3g30oXMoNyO/VS/Vbw==, tableContent=null), ArticleFig(id=1308499181745045742, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455574711066825, language=CN, label=Fig.3, caption=PF induces apoptosis in gastric cancer cells. A, B: Effects of PF on apoptosis in SGC-7901 (A) and HGC-27 (B); C, D: Apoptosis phase distribution in SGC-7901 (C) and HGC-27 (D); E, F: Regulation of apoptosis-related proteins by PF in SGC-7901 (E) and HGC-27 (F). n = 3, $ \stackrel{-}{x} $ ± s. *P < 0.05, **P < 0.01, ***P < 0.001 vs control, figureFileSmall=4jimDKys5oloo8uTgu2iig==, figureFileBig=qsRE3g30oXMoNyO/VS/Vbw==, tableContent=null), ArticleFig(id=1308499181807960303, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455574711066825, language=EN, label=null, caption=null, figureFileSmall=FdGF+vNvk3gOq0VK0nPf8Q==, figureFileBig=7+UJgv6mwOnXvP8Dv9FiuA==, tableContent=null), ArticleFig(id=1308499181875069168, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455574711066825, language=CN, label=Fig.4, caption=Transcriptomic profiling of gastric cancer cells treated with PF, figureFileSmall=FdGF+vNvk3gOq0VK0nPf8Q==, figureFileBig=7+UJgv6mwOnXvP8Dv9FiuA==, tableContent=null), ArticleFig(id=1308499181942178033, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455574711066825, language=EN, label=null, caption=null, figureFileSmall=9HjUgWevmWrikVKfOkUPdA==, figureFileBig=tpUhUecxvF061b+UjXd/mQ==, tableContent=null), ArticleFig(id=1308499182021869810, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455574711066825, language=CN, label=Fig.5, caption=PF modulates the HSP90/Akt/MDM2/p53 signaling pathway. A, B: Molecular docking models of PF with HSP90AA1 (A) and MDM2 (B); C, D: Effects of PF on HSP90/Akt pathway-related protein expression in SGC-7901 (C) and HGC-27 (D). n = 3, $ \stackrel{-}{x} $ ± s. *P < 0.05, **P < 0.01, ***P < 0.001 vs control, figureFileSmall=9HjUgWevmWrikVKfOkUPdA==, figureFileBig=tpUhUecxvF061b+UjXd/mQ==, tableContent=null), ArticleFig(id=1308499182080590067, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455574711066825, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
MoleculeMatched ligand siteFitnessTarget_nameGene_name
PFR(9) R(11) R(10)2.32HPGDS_HUMANHPGDS
PFP(8) R(10) R(9)2.18CHIA_HUMANCHIA
PFH(3) R(11) R(10)2.15BLVRB_HUMANBLVRB
PFH(4) H(3) R(11) R(10)2.09FAS_HUMANFASN
PFH(3) R(10) R(11)2.05AL3A1_HUMANALDH3A1
PFH(4) R(10) R(11)1.95RET_HUMANRET
PFD(2) R(9) R(11)1.94GSK3B_HUMANGSK3B
PFH(3) R(10) R(11)1.94S10A4_HUMANS100A4
PFH(4) R(10) R(11)1.94KC1D_HUMANCSNK1D
PFR(10) R(11) R(9)1.91PDE4D_HUMANPDE4D
PFA(1) R(10) R(9)1.90HS90A_HUMANHSP90AA1
PFH(4) R(10) R(11)1.89MAP2_HUMANMETAP2
PFH(4) R(11) R(10)1.89KC1D_HUMANCSNK1D
PFH(4) R(10) R(11)1.89MDM2_HUMANMDM2
PFR(9) R(10) R(11)1.89CASP6_HUMANCASP6
), ArticleFig(id=1308499182143504628, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455574711066825, language=CN, label=Tab.1, caption=

Molecular docking results of potential target proteins binding to PF

, figureFileSmall=null, figureFileBig=null, tableContent=
MoleculeMatched ligand siteFitnessTarget_nameGene_name
PFR(9) R(11) R(10)2.32HPGDS_HUMANHPGDS
PFP(8) R(10) R(9)2.18CHIA_HUMANCHIA
PFH(3) R(11) R(10)2.15BLVRB_HUMANBLVRB
PFH(4) H(3) R(11) R(10)2.09FAS_HUMANFASN
PFH(3) R(10) R(11)2.05AL3A1_HUMANALDH3A1
PFH(4) R(10) R(11)1.95RET_HUMANRET
PFD(2) R(9) R(11)1.94GSK3B_HUMANGSK3B
PFH(3) R(10) R(11)1.94S10A4_HUMANS100A4
PFH(4) R(10) R(11)1.94KC1D_HUMANCSNK1D
PFR(10) R(11) R(9)1.91PDE4D_HUMANPDE4D
PFA(1) R(10) R(9)1.90HS90A_HUMANHSP90AA1
PFH(4) R(10) R(11)1.89MAP2_HUMANMETAP2
PFH(4) R(11) R(10)1.89KC1D_HUMANCSNK1D
PFH(4) R(10) R(11)1.89MDM2_HUMANMDM2
PFR(9) R(10) R(11)1.89CASP6_HUMANCASP6
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五氟利多通过HSP90/Akt/MDM2/p53信号通路抑制胃癌细胞生物学行为的研究
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王珮郦 1, 2 , 陈奇峰 1, 2 , 霍艺萱 2 , 王家瑞 5 , 贺蓉 2 , 蒋利和 1, 2, 3, 4, *
药学学报 | 研究论文 2025,60(8): 2528-2534
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药学学报 |研究论文 2025 , 60 (8) : 2528 -2534
五氟利多通过HSP90/Akt/MDM2/p53信号通路抑制胃癌细胞生物学行为的研究
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affiliation=null, department=null, xref=1, 2, 3, 4, *, address=1Medical School of Guangxi University, Nanning 530004, China
2Basic Medical College of Youjiang Medical University for Nationalities, Baise 533000, China
3Guangxi Key Laboratory for Pharmaceutical Molecular Discovery and Druggability Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China
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2右江民族医学院基础医学院, 广西 百色 533000
3广西药物分子发现与成药性优化重点实验室 (桂林医科大学药学院), 广西 桂林 541199
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王珮郦1, 2, 陈奇峰1, 2, 霍艺萱2, 王家瑞5, 贺蓉2, 蒋利和1, 2, 3, 4, *
作者信息
  • 1广西大学医学院, 广西 南宁 530004
  • 2右江民族医学院基础医学院, 广西 百色 533000
  • 3广西药物分子发现与成药性优化重点实验室 (桂林医科大学药学院), 广西 桂林 541199
  • 4广西高校人体发育与疾病研究重点实验室 (广西医科大学), 广西 南宁 530021
  • 5右江民族医学院医学检验学院, 广西 百色 533000
通讯作者:
蒋利和, E-mail:
作者简介:

作者贡献:

王珮郦、陈奇峰共同承担实验研究与数据分析的工作; 王珮郦完成论文撰写与初步修订; 陈奇峰、霍艺萱分析转录组学测序数据; 王家瑞、贺蓉负责文献检索与综述; 蒋利和全程指导课题研究、提供经费支持, 并对论文进行审阅与关键性修订。

The inhibition of biological behavior of gastric cancer cells by penfluridol through HSP90/Akt/MDM2/p53 signaling pathway
Pei-li WANG1, 2, Qi-feng CHEN1, 2, Yi-xuan HUO2, Jia-rui WANG5, Rong HE2, Li-he JIANG1, 2, 3, 4, *
Affiliations
  • 1Medical School of Guangxi University, Nanning 530004, China
  • 2Basic Medical College of Youjiang Medical University for Nationalities, Baise 533000, China
  • 3Guangxi Key Laboratory for Pharmaceutical Molecular Discovery and Druggability Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China
  • 4Guangxi Colleges and Universities Key Laboratory of Human Development and Disease Research (Guangxi Medical University), Nanning 530021, China
  • 5School of Medical Laboratory Science, Youjiang Medical University for Nationalities, Baise 533000, China
出版时间: 2025-08-12 doi: 10.16438/j.0513-4870.2025-0058
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本研究探讨了抗精神病药物五氟利多(penfluridol, PF) 在胃癌治疗中的抗肿瘤活性及其作用机制。通过CCK-8法、集落形成实验、划痕愈合实验、Transwell迁移实验、Hoechst 33342染色和流式细胞术等系列检测发现, 五氟利多可显著抑制SGC-7901和HGC-27胃癌细胞的增殖与迁移能力, 并呈现浓度依赖性诱导细胞凋亡的特征。为进一步揭示其作用机制, 结合转录组学分析与分子对接技术发现, 五氟利多能与热休克蛋白90 (heat shock protein 90, HSP90) 和鼠双微体2 (MDM2 proto-oncogene, MDM2) 蛋白形成稳定结合构象。Western blot实验证实五氟利多抑制了热休克蛋白90/蛋白激酶B/鼠双微体2/肿瘤蛋白p53信号通路, 其中HSP90表达水平下降伴随p53蛋白显著上调。研究结果表明, 五氟利多通过多种机制抑制胃癌细胞恶性生物学行为, 其调控网络涉及关键肿瘤信号通路, 为五氟利多作为潜在的胃癌治疗药物提供了实验依据。

胃癌  /  药物再利用  /  五氟利多  /  分子对接  /  热休克蛋白90  /  转录组学

This study investigated the antitumor activity and molecular mechanisms of penfluridol (PF), an antipsychotic drug, in gastric cancer treatment. In vitro assays including CCK-8, colony formation, wound healing, Transwell migration, Hoechst 33342 staining, and flow cytometry demonstrated that penfluridol significantly inhibited proliferation and migration of SGC-7901 and HGC-27 gastric cancer cells in a concentration-dependent manner, while inducing apoptosis. Transcriptomic profiling combined with molecular docking revealed stable binding conformations between penfluridol and heat shock protein 90 (HSP90) or mouse double minute 2 (MDM2). Western blot analysis further confirmed that penfluridol suppressed the HSP90/protein kinase B/MDM2/tumor protein p53 (HSP90/Akt/MDM2/p53) pathway, characterized by decreased HSP90 expression and concomitant upregulation of p53 protein. These findings collectively indicate that penfluridol exerts multifaceted antitumor effects by targeting key oncogenic pathways, providing experimental evidence for repurposing this antipsychotic agent as a potential therapeutic strategy against gastric cancer.

gastric cancer  /  drug repurposing  /  penfluridol  /  molecular docking  /  heat shock protein 90  /  transcriptomics
王珮郦, 陈奇峰, 霍艺萱, 王家瑞, 贺蓉, 蒋利和. 五氟利多通过HSP90/Akt/MDM2/p53信号通路抑制胃癌细胞生物学行为的研究. 药学学报, 2025 , 60 (8) : 2528 -2534 . DOI: 10.16438/j.0513-4870.2025-0058
Pei-li WANG, Qi-feng CHEN, Yi-xuan HUO, Jia-rui WANG, Rong HE, Li-he JIANG. The inhibition of biological behavior of gastric cancer cells by penfluridol through HSP90/Akt/MDM2/p53 signaling pathway[J]. Acta Pharmaceutica Sinica, 2025 , 60 (8) : 2528 -2534 . DOI: 10.16438/j.0513-4870.2025-0058
正文
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胃癌作为全球范围内高发的消化道恶性肿瘤, 其疾病负担与不良预后构成重大公共卫生挑战。流行病学数据显示, 胃癌年新发病例占全球癌症总发病数的5%, 相关死亡率占癌症死亡总数的7%[1]。这一态势在中国尤为严峻, 我国胃癌发病率与死亡率分别占据全球数据的37%和39.4%, 位列癌症致死原因第三位。尽管诊疗技术持续进步, 进展期胃癌患者的5年生存率仍低于30%[2]。胃癌细胞的高转移倾向和化疗耐药性是导致治疗失败的重要因素。报道显示, 伴有淋巴结转移患者的5年生存率较无转移者显著降低[3], 这从临床结局层面提示抑制肿瘤侵袭转移等恶性生物学行为在改善预后中的关键作用。
由于新药开发存在客观局限, 抗肿瘤新药上市进展缓慢且费用高昂, 因此通过“药物再利用”方案, 研究传统药物的抗肿瘤效果成为一种有效且成本可控的途径[4]。五氟利多(penfluridol, PF) 是一种长效多巴胺受体拮抗剂, 不良反应小、半衰期长, 主要用于治疗慢性精神分裂症, 并具有镇吐、抗焦虑、抗菌和抗炎等多种作用[5]。多项研究报道了五氟利多的抗肿瘤活性: 通过自噬体累积或抑制线粒体功能, 五氟利多联合糖酵解抑制剂可有效抑制肺癌细胞的增殖[6, 7]; 在食管癌中, 五氟利多通过直接靶向磷酸果糖激酶并诱导癌细胞凋亡, 发挥抗癌作用[8]。目前, 五氟利多在胃癌中的影响尚未阐明。本研究探索五氟利多抗胃癌活性, 采用多种实验方法探究其对胃癌细胞生长、迁移和凋亡的作用, 并借用转录组学技术与分子对接技术揭示其可能的分子机制。
材料与方法
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药品与试剂  五氟利多购自美国MedChemExpress公司, 批号: HY-B1077-17270, 纯度≥ 99.93%; 兔多克隆抗体: E-钙黏蛋白(E-cadherin, E-cad) (货号: 20874-1-AP)、N-钙黏蛋白(N-cadherin, N-cad) (货号: 22018-1-AP)、波形蛋白(vimentin) (货号: 10366-1-AP)、剪切型半胱天冬酶3 (cleaved-caspase3) (货号: 25128-1-AP)、聚腺苷二磷酸核糖聚合酶(poly ADP-ribose polymerase, PARP) (货号: 13371-1-AP)、热休克蛋白90 (heat shock protein 90, HSP90) (货号: 13171-1-AP)、双微体2同源物(MDM2 proto-oncogene, MDM2) (货号: 27883-1-AP)、肿瘤蛋白p53 (tumor protein p53, p53) (货号: 10442-1-AP)、鼠单克隆抗体: 半胱天冬酶3 (caspase3) (货号: 66470-2-Ig)、剪切型聚腺苷二磷酸核糖聚合酶(cleaved-PARP) (货号: 60555-1-Ig)、磷酸化蛋白激酶B (phosphorylated protein kinase B, p-Akt) (货号: 66444-1-Ig), 武汉三鹰生物技术有限公司; 甘油醛-3-磷酸脱氢酶(glyceraldehyde-3-phosphate dehydrogenase, GAPDH) 抗体(货号: BK-S65165), 上海帛科生物技术有限公司; β-肌动蛋白(beta-actin, β-actin) 抗体(货号: AF5001)、辣根过氧化物酶标记山羊抗兔IgG(H+L) (货号: A0208)、辣根过氧化物酶标记山羊抗小鼠IgG(H+L) (货号: A0216), 上海碧云天生物技术股份有限公司; 胎牛血清(货号: A511-001), 上海双洳公司; Hoechst 33342试剂(货号: B8040)、高效RIPA裂解液(组织/细胞) (货号: R0010), 北京索莱宝科技有限公司; Annexin V-FITC流式试剂盒(货号: 556547), 美国BD公司; TRIzol试剂(货号: 15596018CN)、RPMI 1640培养基(货号: 11875119), 美国赛默飞公司。
主要仪器  二氧化碳培养箱(型号: HF90), 上海市力新仪器有限公司; 普通光学显微镜(型号: OLYMPUS-BX51), 日本奥林巴斯公司; 倒置荧光显微镜(型号: Nikon Ti), 日本尼康公司; 酶标仪(型号: Tristar LB941), 德国伯托公司; 流式细胞分析仪(型号: Attune NxT), 美国赛默飞公司; 超低温冰箱(型号: DW-86L386), 海尔公司; 低速台式离心机(型号: L420-A), 湖南湘仪公司; 化学发光成像仪(型号: Tanon-4800), 上海天能公司。
细胞培养  本研究使用人胃癌细胞为SGC-7901细胞和HGC-27细胞, 来自中国科学院上海细胞所。配置90% RPMI 1640基础培养基+10%胎牛血清+1%青霉素-链霉素双抗试剂作为完全培养基, 于37 ℃、5% CO2的培养箱中无菌培养。
CCK-8实验  将细胞以每孔3 000个接种至96孔板, 使用0、2、4、6、8、10 μmol·L-1五氟利多进行处理。分别处理24、48、72 h后, 弃去含药培养基。PBS洗涤细胞, 加入含10% CCK-8试剂的无血清培养基, 避光孵育2 h后测量450 nm吸光度(A) 值。实验重复3次。细胞活力(%) = (A实验组/A对照组)×100%。
集落形成实验  将细胞以每孔3×103个接种至6孔板中培养24 h, 更换含0、1、2、3 μmol·L-1五氟利多的新鲜培养基培养2周。固定染色, 记录各孔集落数量。使用ImageJ软件统计数据, 计算各组集落形成率。重复3次。
划痕实验  将细胞以每孔2.5×105个接种于6孔板中培养至细胞密度95%以上进行划痕处理。PBS洗涤细胞后, 记录划痕面积。加入含五氟利多的无血清培养基培养24 h (SGC-7901: 0、4、8、12 μmol·L-1; HGC-27: 0、3、6、9 μmol·L-1), 观察同视野划痕面积。使用ImageJ计算愈合率。重复3次。
Transwell迁移实验  使用无血清培养基将细胞以每孔10 000个接种于上室, 下室加入含五氟利多的培养基(SGC-7901: 0、4、8、12 μmol·L-1; HGC-27: 0、3、6、9 μmol·L-1), 培养24 h。固定染色, 记录穿膜细胞数量。用ImageJ计数, 重复3次。
Hoechst 33342荧光实验  将细胞浓度调整至每孔2×105个, 接种至6孔板中培养24 h。PBS冲洗后, 加入含五氟利多的培养基(SGC-7901: 0、4、8、12 μmol·L-1; HGC-27: 0、3、6、9 μmol·L-1), 处理24 h。染色、清洗。使用荧光显微镜记录随机视野下细胞凋亡情况, 保持全组图像采集参数一致。扣除背景荧光后, 使用ImageJ测定细胞的平均荧光强度, 计算视野内全体细胞荧光强度均值。每组重复3次独立实验, 采用相对荧光强度对结果进行定量分析。
流式细胞术  将细胞以每孔2×105个接种至6孔板, 24 h后更换培养基并加入含五氟利多的培养基(SGC-7901: 0、4、8、12 μmol·L-1; HGC-27: 0、3、6、9 μmol·L-1), 培养24 h。洗涤细胞, 胰酶消化后离心。加入Annexin V-FITC和PI染料避光静置染色。使用流式细胞仪测定细胞凋亡率。重复3次。
Western blot法检测人胃癌细胞相关蛋白表达  在对数生长期培养细胞加入含五氟利多的培养基(SGC-7901: 0、4、8、12 μmol·L-1; HGC-27: 0、3、6、9 μmol·L-1) 处理24 h, 观察细胞状态。冰上裂解细胞获取总蛋白, BCA法测定蛋白浓度并调整上样量, 煮沸变性后于-20 ℃保存。取上清加入SDS-PAGE凝胶后电泳。使用湿法转膜将蛋白转移至PVDF膜。室温封闭2 h后, 一抗4 ℃孵育过夜。次日加入二抗震荡孵育1 h后显影, ImageJ软件计算条带灰度值并绘制统计图。实验重复3次。
转录组测序  将SGC-7901细胞按每孔2×105个接种至6孔板中培养24 h后, 加入0和8 μmol·L-1五氟利多处理24 h。洗涤细胞后胰酶消化, 离心重悬, Trizol裂解, 干冰保存, 送至北京百迈客生物公司进行测序。实验设3组平行。
蛋白筛选与分子对接  为筛选penfluridol的潜在作用蛋白, 使用Schrodinger 2021-1软件的LigPrep模块进行质子化和结构优化, 并使用已有药效团库进行靶点筛选。设置目标分子生成构象200个, 筛选分值超过2的蛋白。随后利用AutoDock Vina 1.1.2进行分子对接, 并使用PyMol软件修饰分子结构, 确定对接中心点。对接后, 利用PyMol可视化对接结果。
统计学分析  所有实验重复3次, 使用SPSS 25.0软件进行单因素方差分析, P < 0.05说明具有显著性差异。采用GraphPad Prism 9绘制和展示数据。
结果
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1　五氟利多对胃癌细胞增殖与集落形成能力的抑制作用
采用0、2、4、6、8、10 μmol·L-1的五氟利多处理胃癌细胞(SGC-7901和HGC-27), 通过CCK-8法检测发现: 随着五氟利多浓度升高, 两株细胞在24、48、72 h的增殖活力均呈浓度依赖性下降(图1A、B)。经计算得, 五氟利多作用于SGC-7901和HGC-27细胞24 h的IC50分别为7.98和6.27 μmol·L-1。因此, 选择浓度为0、4、8、12 μmol·L-1 (SGC-7901) 和0、3、6、9 μmol·L-1 (HGC-27) 的五氟利多处理细胞(分别作为对照组, 低、中、高剂量组) 进行后续迁移、侵袭等实验。
为评估五氟利多在较低浓度下长期作用对细胞增殖潜能的抑制效果, 采用0、1、2、3 μmol·L-1五氟利多进行平板克隆实验。结果显示, 3 μmol·L-1五氟利多可显著抑制两株细胞的集落形成能力(图1C、D)。
2　五氟利多对胃癌细胞划痕愈合与迁移能力的抑制作用
为探究五氟利多对胃癌细胞转移的影响, 采用划痕实验和Transwell迁移实验评估其作用。结果显示: 经24 h处理, 五氟利多显著抑制SGC-7901和HGC-27细胞的划痕愈合能力(图2A、C), 其中12 μmol·L-1 (SGC-7901) 和9 μmol·L-1 (HGC-27) 五氟利多处理组的抑制作用最为显著; 同时, Transwell实验表明, 随五氟利多浓度升高, 两株细胞的穿膜数量均显著减少(图2B、D)。Western blot分析上皮-间质转化(epithelial-mesenchymal transition, EMT) 标志物显示, 五氟利多处理上调E-cadherin表达, 下调N-cadherin和vimentin表达(图2E、F), 进一步证实其通过阻断EMT进程抑制胃癌细胞转移。
3　五氟利多对胃癌细胞凋亡的诱导作用
采用Hoechst 33342染色检测发现, 五氟利多处理24 h后, SGC-7901和HGC-27细胞的荧光强度显著增强, 且强荧光细胞比例随浓度升高而增加(图3)。流式细胞术显示, 五氟利多显著提升两株细胞的总凋亡率, 且最高浓度处理组(SGC-7901: 12 μmol·L-1; HGC-27: 9 μmol·L-1) 的早期及晚期凋亡比例均显著高于对照组。Western blot结果表明, 随五氟利多浓度升高, cleaved-caspase3和cleaved-PARP表达上调, 同时caspase3和PARP表达下调。上述数据证明, 五氟利多以浓度依赖的方式诱导胃癌细胞凋亡。
4　五氟利多处理胃癌细胞前后的转录组学分析
为探究五氟利多的分子机制, 采用微阵列技术分析SGC-7901细胞经五氟利多处理24 h后的转录组。共鉴定292个差异基因, 包括79个上调和213个下调。KEGG通路富集分析发现PI3K-Akt信号通路在差异基因中占比较高(图4)。该通路作为调控细胞增殖、分化与凋亡的核心信号轴, 其关键效应分子Akt的异常活性已被广泛报道与肿瘤发生发展密切相关[9]。
5　五氟利多对HSP90/Akt/MDM2/p53通路蛋白的影响
基于药效团数据库和差异基因筛选潜在靶点, 表1按fitness评分(满分3) 排序显示前15名靶点。HSP90作为Akt的上游分子伴侣, 稳定Akt构象增强其活性。分子对接显示, HSP90/Akt/MDM2/p53通路中的HSP90AA1和MDM2能与五氟利多形成复合物, 小分子分别结合于二者活性口袋, 并与MDM2的VAL-93、HSP90AA1的ASN-51形成氢键以维持结合。Western blot表明, 五氟利多浓度升高, HSP90、p-Akt及MDM2表达降低, 同时p53上调(图5)。上述结果提示, 五氟利多通过干预HSP90/Akt/MDM2/p53通路发挥作用, 验证了靶点预测假设。
讨论
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增殖、迁移及抗凋亡是癌细胞的常见恶性表型, 受多信号通路调控, 抑制这些行为有助于改善患者预后[10]。五氟利多为经典抗精神病药, 不良反应小且半衰期长, 近年研究报道其抗肿瘤活性[11]。本研究通过CCK-8、集落形成、划痕/Transwell迁移及Hoechst/流式实验, 证实其以浓度依赖的方式抑制胃癌细胞增殖、迁移并诱导凋亡。
基于胃癌细胞转录组学分析, KEGG富集显示五氟利多处理后PI3K-Akt通路显著富集。Akt的过度磷酸化已被证实与胃癌患者化疗耐药性和不良预后显著相关[12, 13], 提示其作为关键治疗靶点的潜力。在最可能与五氟利多结合的药物靶点蛋白中, HSP90作为调控肿瘤转移、侵袭的关键分子伴侣, 可维持Akt活性, 促进MDM2介导的p53降解, 从而促进癌细胞增殖[14, 15]。分子对接显示, 五氟利多与HSP90AA1、MDM2亲和力较高; Western blot证实随五氟利多浓度升高, HSP90、p-Akt、MDM2蛋白表达显著下调, 提示五氟利多与靶标蛋白结合紧密, 并抑制了Akt/MDM2/p53通路的激活。
本研究的不足之处在于: 虽然证实了五氟利多的抗胃癌活性, 并发现药物浓度增加能够增强对EMT相关信号的抑制, 降低肿瘤细胞的迁移能力, 但这种抑制作用与EMT过程的具体分子机制仍需进一步研究。通过转录组学、药靶预测和分子对接, 获得了Akt/MDM2/p53通路的相关线索, 但五氟利多是否通过靶向HSP90蛋白、破坏其与Akt的结合来抑制该通路, 还需要更多实验验证。此外, 本研究仅基于体外细胞实验, 五氟利多在体内的抗胃癌活性及其对整体生理系统的影响, 仍需通过动物实验和临床试验进一步探索。未来研究可以进一步探讨五氟利多在体内外模型中的作用机制, 以及与其他抗癌药物的协同作用, 以更全面地评估其在胃癌治疗中的潜力。
综上所述, 本研究通过多项实验证实, 五氟利多能够显著抑制胃癌细胞增殖与迁移, 并诱导细胞凋亡, 且其作用呈浓度依赖性。结合转录组学与分子对接分析, 本研究进一步揭示五氟利多可能通过靶向HSP90/Akt/MDM2/p53信号通路发挥抗癌作用, 为其作为潜在胃癌治疗药物提供了实验依据。尽管研究存在一定局限性, 但进一步的体内实验与临床验证将有助于明确其应用前景。

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doi: 10.16438/j.0513-4870.2025-0058
  • 接收时间：2025-01-16
  • 首发时间：2026-09-20
  • 出版时间：2025-08-12
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  • 收稿日期：2025-01-16
  • 修回日期：2025-03-28
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    1广西大学医学院, 广西 南宁 530004
    2右江民族医学院基础医学院, 广西 百色 533000
    3广西药物分子发现与成药性优化重点实验室 (桂林医科大学药学院), 广西 桂林 541199
    4广西高校人体发育与疾病研究重点实验室 (广西医科大学), 广西 南宁 530021
    5右江民族医学院医学检验学院, 广西 百色 533000

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2种不同金属材料的力学参数
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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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