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Article(id=1308455402249679033, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308455335962894804, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0061, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1737043200000, receivedDateStr=2025-01-17, revisedDate=1743436800000, revisedDateStr=2025-04-01, acceptedDate=null, acceptedDateStr=null, onlineDate=1789889677821, onlineDateStr=2026-09-20, pubDate=1749657600000, pubDateStr=2025-06-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789889677821, onlineIssueDateStr=2026-09-20, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789889677821, creator=13701087609, updateTime=1789889677821, updator=13701087609, issue=Issue{id=1308455335962894804, tenantId=1146029695717560320, journalId=1189982191388893191, year='2025', volume='60', issue='6', pageStart='1573', pageEnd='1964', issueExtLink='null', onlineDate='null', pubDate='1749657600000', pubDateStr='2025-06-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789889662017, creator='13701087609', updateTime=1789893590327, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308471812564734358, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308455335962894804, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308471812564734359, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308455335962894804, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1739, endPage=1745, ext={EN=ArticleExt(id=1308455402471977146, articleId=1308455402249679033, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=The efficacy and mechanism of the novel small molecule degradation agent LS-13 targeting ARfl/ARv7 to inhibit enzalutamide resistant in prostate cancer, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Enzalutamide resistance (ENZR) is the most common issue in castration-resistant prostate cancer (CRPC). After a period of treatment with the second-generation androgen receptor (AR) inhibitor enzalutamide (ENZ), patients develop resistance to ENZ, posing a serious threat to male health. However, there are currently no effective drugs for treating prostate cancer patients with ENZ resistance. Based on the structural optimization and modification of enzalutamide, and through molecular biological methods such as cell viability assays, colony formation, cell apoptosis detection, Western blot and other molecular biology techniques, it was discovered that the half-maximal inhibitory concentration values of LS-13 for prostate cancer LNCaP-ENZR and 22RV1 cells are 17.09 and 19.90 μmol·L-1, respectively. Subsequently, after treating the resistant cell lines with 0.1, 1, 5, and 10 μmol·L-1 of LS-13 for 12 days, the observation results indicated that LS-13 could inhibit the in vitro clonal formation of LNCaP-ENZR and 22RV1 cells in a dose-dependent manner. Furthermore, after treating the resistant cell lines with 1.25, 2.5, 5, and 10 μmol·L-1 of LS-13 for 72 h, the results of flow cytometry also showed that LS-13 could promote apoptosis of the resistant cell lines in a dose-dependent manner. Furthermore, under the same concentration conditions described above, after LS-13 treatment of 22RV1 cells for 24 h, it was found that their migration speed was significantly slowed down (P < 0.05). These results collectively indicate that the small molecule compound LS-13 has a pronounced effect in inhibiting ENZR. Further mechanism studies found that LS-13 can target ARfl/ARv7 and promote its protein degradation, inhibit the transcription levels of AR-downstream target genes, thereby suppressing ENZR cell proliferation and promoting apoptosis. This study provides a candidate compound for targeting ARfl/ARv7 to overcome ENZ resistance.

, authors=Zheng-yi HAN1, Yan LIANG4, Peng CAO1, 2, Zhen-yu YIN3, *, Yan LI2, *, authorsList=Zheng-yi HAN, Yan LIANG, Peng CAO, Zhen-yu YIN, Yan LI, authorCompany=null, correspAuthors=Zhen-yu YIN, Yan LI, 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=1308455403713491141, articleId=1308455402249679033, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=靶向ARfl/ARv7新型小分子降解剂LS-13抑制前列腺癌恩杂鲁胺耐药的药效及机制研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

恩杂鲁胺耐药(enzalutamide resistance, ENZR) 是去势抵抗性前列腺癌(castration-resistant prostate cancer, CRPC) 最为常见的问题, 患者在使用第二代雄激素受体(androgen receptor, AR) 抑制剂恩杂鲁胺(enzalutamide, ENZ) 治疗一段时间后, 出现对ENZ的抵抗, 严重威胁男性健康。但临床尚无治疗前列腺癌ENZ耐药的有效药物。前期基于对恩杂鲁胺的结构优化与改造, 并通过细胞活力实验、克隆形成、细胞凋亡检测及蛋白质印迹等分子生物学手段检测发现: LS-13对前列腺癌LNCaP-ENZR和22RV1细胞的半数抑制浓度值分别为17.09和19.90 μmol·L-1。随后, 通过使用0.1、1、5、10 μmol·L-1 LS-13处理耐药细胞株12天后, 观察结果显示LS-13能够以剂量依赖性方式抑制LNCaP-ENZR和22RV1细胞的体外克隆形成。此外, 经过1.25、2.5、5、10 μmol·L-1 LS-13处理耐药细胞株72 h后, 流式细胞术的结果也显示LS-13能够以剂量依赖性方式促进耐药细胞株的凋亡。进一步地, 在上述相同浓度条件下, LS-13处理22RV1细胞24 h后, 发现其迁移速度显著减缓(P < 0.05)。这些结果共同表明, 小分子化合物LS-13具有明显抑制ENZR的作用。进一步机制探讨发现, LS-13可通过靶向ARfl/ARv7并促进其蛋白降解, 抑制AR对下游靶基因的转录水平, 进而抑制ENZR细胞增殖, 促进细胞凋亡。该研究为靶向ARfl/ARv7降解, 克服ENZ耐药提供候选化合物。

, authors=韩正义1, 梁艳4, 曹鹏1, 2, 尹震宇3, *, 李岩2, *, authorsList=韩正义, 梁艳, 曹鹏, 尹震宇, 李岩, authorCompany=null, correspAuthors=尹震宇, 李岩, authorNote=

作者贡献:

韩正义负责药理实验和文章的撰写; 李岩负责实验设计、文章修改与审核; 梁艳负责对文章修改和临床治疗指南分析指导; 曹鹏和尹震宇负责对实验进行指导。

, correspAuthorsNote=
尹震宇, E-mail:
李岩, E-mail:
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A: Chemical structure of LS-13; B: Half-inhibitory concentration values of LS-13 on LNCaP-ENZR and 22RV1 cells; C: LNCaP-ENZR and 22RV1 cells were treated with LS-13 at concentrations of 0.1, 1, 5, 10 μmol·L-1 and 10 μmol L-1 enzalutamide (ENZ) for 12 days, and the colony formation assay was photographed and recorded. ENZR: Enzalutamide resistance. Circle diagram: 1×, block diagram: 5×, figureFileSmall=e1bxB6Z2wCoK+1L9/V1xAw==, figureFileBig=iY/EG+rDyyWmDigdG2Y2bg==, tableContent=null), ArticleFig(id=1308497847486611586, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455402249679033, language=EN, label=null, caption=null, figureFileSmall=ftaBpyxLLWuGj0MvtUJYFw==, figureFileBig=9Dqc5F33Rcx06yeXAdVZgQ==, tableContent=null), ArticleFig(id=1308497847587274883, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455402249679033, language=CN, label=Fig.2, caption=Compound LS-13 promotes apoptosis in ENZR cell lines LNCaP-ENZR and 22RV1. A: Cell apoptosis was detected by flow cytometry after treating LNCaP-ENZR cells with 1.25, 2.5, 5, 10 μmol·L-1 LS-13 and 10 μmol L-1 ENZ for 72 h; B: Cell apoptosis was detected by flow cytometry after treating 22RV1 cells with 1.25, 2.5, 5, 10 μmol·L-1 LS-13 and 10 μmol L-1 ENZ for 72 h; C: The quantification of figure A; D: The quantification of figure B. n = 3, mean ± SEM. *P < 0.05, **P < 0.01. ns indicates no statistically significant difference, figureFileSmall=ftaBpyxLLWuGj0MvtUJYFw==, figureFileBig=9Dqc5F33Rcx06yeXAdVZgQ==, tableContent=null), ArticleFig(id=1308497847671160964, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455402249679033, language=EN, label=null, caption=null, figureFileSmall=YO4Eom3Vopk24tmrJRuQKg==, figureFileBig=xt5MKT7vZcWJaB+nMsbrZA==, tableContent=null), ArticleFig(id=1308497847742464133, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455402249679033, language=CN, label=Fig.3, caption=LS-13 inhibits the horizontal migration of 22RV1 cells in a dose-dependent manner. A: After treated with 1.25, 2.5, 5, 10 μmol·L-1 LS-13 and 10 μmol·L-1 ENZ for 0 and 24 h, the scratch of 22RV1 cells were record. Scale bar: 100 μm, 40 μm; B: The statistical results of scratch width of 22RV1 cells after treatment for 24 h in figure A. n = 3, mean ± SEM. *P < 0.05, ***P < 0.001, figureFileSmall=YO4Eom3Vopk24tmrJRuQKg==, figureFileBig=xt5MKT7vZcWJaB+nMsbrZA==, tableContent=null), ArticleFig(id=1308497847817961606, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455402249679033, language=EN, label=null, caption=null, figureFileSmall=A5kf7W+vKd1EBTnziV33kw==, figureFileBig=jGtsixKmsQNa+CE9OcV74Q==, tableContent=null), ArticleFig(id=1308497849067864199, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455402249679033, language=CN, label=Fig.4, caption=The compound LS-13 inhibits androgen receptor (AR) expression and accelerats AR degradation. A: The docking of LS-13 and AR (Blue: LS-13); B: The protein levels of ARfl and ARv7 in 22RV1 cells, which were treated with DMSO, LS-13 (5 and 10 μmol·L-1), and ENZ (10 μmol·L-1) for 48 h; C, D: The protein quantification of ARfl (C) and ARv7 (D) (relative to β-actin); E: The protein levels of ARfl and ARv7 in 22RV1 cells, with the treatment of cycloheximide (CHX, 50 μg·mL-1) plus LS-13 (10 μmol·L-1) or CHX only for 0, 0.5, 1, 2, 4 and 8 h. n = 3, mean ± SEM. ****P < 0.000 1, figureFileSmall=A5kf7W+vKd1EBTnziV33kw==, figureFileBig=jGtsixKmsQNa+CE9OcV74Q==, tableContent=null), ArticleFig(id=1308497849155944584, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455402249679033, language=EN, label=null, caption=null, figureFileSmall=4srRBSsNHglu2gTgoGAovw==, figureFileBig=YsoJ1Ew00wYwyKDO6FcpgQ==, tableContent=null), ArticleFig(id=1308497849256607881, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455402249679033, language=CN, label=Fig.5, caption=The compound LS-13 inhibits transcription function of AR, and downregulates the mRNA levels of downstream target genes of AR. A: The mRNA levels of ARfl, ARv7, TMPRSS2 and KLK3 in LNCaP-ENZR cells, with the treatment of 5, 10 μmol·L-1 LS-13 and 10 μmol·L-1 ENZ for 24 h; B: The mRNA levels of ARfl, ARv7, TMPRSS2 and KLK3 in 22RV1 cells, with the treatment of 5, 10 μmol·L-1 LS-13 and 10 μmol·L-1 ENZ for 24 h. n = 3, mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.000 1, figureFileSmall=4srRBSsNHglu2gTgoGAovw==, figureFileBig=YsoJ1Ew00wYwyKDO6FcpgQ==, tableContent=null), ArticleFig(id=1308497849344688266, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455402249679033, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
GenePrimer sequence (5′ to 3′)
ARflForwardCCAGGGACCATGTTTTGCC
ReverseCGAAGACGACAAGATGGACAA
ARv7ForwardCCATCTTGTCGTCTTCGGAAATGTTA
ReverseTTTGAATGAGGCAAGTCAGCCTTTCT
TMPRSS2ForwardGTCCCCACTGTCTACGAGGT
ReverseCAGACGACGGGGTTGGAAG
KLK3ForwardCACAGGCCAGGTATTTCAGGT
ReverseGAGGCTCATATCGTAGAGCGG
), ArticleFig(id=1308497849453740171, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308455402249679033, language=CN, label=Tab.1, caption=

Sequence of RT-PCR primers

, figureFileSmall=null, figureFileBig=null, tableContent=
GenePrimer sequence (5′ to 3′)
ARflForwardCCAGGGACCATGTTTTGCC
ReverseCGAAGACGACAAGATGGACAA
ARv7ForwardCCATCTTGTCGTCTTCGGAAATGTTA
ReverseTTTGAATGAGGCAAGTCAGCCTTTCT
TMPRSS2ForwardGTCCCCACTGTCTACGAGGT
ReverseCAGACGACGGGGTTGGAAG
KLK3ForwardCACAGGCCAGGTATTTCAGGT
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靶向ARfl/ARv7新型小分子降解剂LS-13抑制前列腺癌恩杂鲁胺耐药的药效及机制研究
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韩正义 1 , 梁艳 4 , 曹鹏 1, 2 , 尹震宇 3, * , 李岩 2, *
药学学报 | 研究论文 2025,60(6): 1739-1745
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药学学报 |研究论文 2025 , 60 (6) : 1739 -1745
靶向ARfl/ARv7新型小分子降解剂LS-13抑制前列腺癌恩杂鲁胺耐药的药效及机制研究
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韩正义1, 梁艳4, 曹鹏1, 2, 尹震宇3, * , 李岩2, *
作者信息
  • 1南京中医药大学药学院, 江苏 南京 210023
  • 2南京中医药大学中药制药过程控制与智能制造技术全国重点实验室, 江苏 南京 210023
  • 3南京中医药大学鼓楼临床医学院, 江苏 南京 210008
  • 4南京大学医学院附属金陵医院/东部战区总医院, 江苏 南京 210007
通讯作者:
尹震宇, E-mail:
李岩, E-mail:
作者简介:

作者贡献:

韩正义负责药理实验和文章的撰写; 李岩负责实验设计、文章修改与审核; 梁艳负责对文章修改和临床治疗指南分析指导; 曹鹏和尹震宇负责对实验进行指导。

The efficacy and mechanism of the novel small molecule degradation agent LS-13 targeting ARfl/ARv7 to inhibit enzalutamide resistant in prostate cancer
Zheng-yi HAN1, Yan LIANG4, Peng CAO1, 2, Zhen-yu YIN3, * , Yan LI2, *
Affiliations
  • 1School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
  • 2National Key Laboratory of Process Control and Intelligent Manufacturing Technology for Traditional Chinese Medicine Pharmaceutical Production, Nanjing University of Chinese Medicine, Nanjing 210023, China
  • 3Gulou Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210008, China
  • 4Affiliated Jinling Hospital, Medical School of Nanjing University/General Hospital of Eastern Theater Command, Nanjing 210007, China
出版时间: 2025-06-12 doi: 10.16438/j.0513-4870.2025-0061
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摘要
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恩杂鲁胺耐药(enzalutamide resistance, ENZR) 是去势抵抗性前列腺癌(castration-resistant prostate cancer, CRPC) 最为常见的问题, 患者在使用第二代雄激素受体(androgen receptor, AR) 抑制剂恩杂鲁胺(enzalutamide, ENZ) 治疗一段时间后, 出现对ENZ的抵抗, 严重威胁男性健康。但临床尚无治疗前列腺癌ENZ耐药的有效药物。前期基于对恩杂鲁胺的结构优化与改造, 并通过细胞活力实验、克隆形成、细胞凋亡检测及蛋白质印迹等分子生物学手段检测发现: LS-13对前列腺癌LNCaP-ENZR和22RV1细胞的半数抑制浓度值分别为17.09和19.90 μmol·L-1。随后, 通过使用0.1、1、5、10 μmol·L-1 LS-13处理耐药细胞株12天后, 观察结果显示LS-13能够以剂量依赖性方式抑制LNCaP-ENZR和22RV1细胞的体外克隆形成。此外, 经过1.25、2.5、5、10 μmol·L-1 LS-13处理耐药细胞株72 h后, 流式细胞术的结果也显示LS-13能够以剂量依赖性方式促进耐药细胞株的凋亡。进一步地, 在上述相同浓度条件下, LS-13处理22RV1细胞24 h后, 发现其迁移速度显著减缓(P < 0.05)。这些结果共同表明, 小分子化合物LS-13具有明显抑制ENZR的作用。进一步机制探讨发现, LS-13可通过靶向ARfl/ARv7并促进其蛋白降解, 抑制AR对下游靶基因的转录水平, 进而抑制ENZR细胞增殖, 促进细胞凋亡。该研究为靶向ARfl/ARv7降解, 克服ENZ耐药提供候选化合物。

前列腺癌  /  耐药性  /  恩杂鲁胺  /  降解  /  雄激素受体

Enzalutamide resistance (ENZR) is the most common issue in castration-resistant prostate cancer (CRPC). After a period of treatment with the second-generation androgen receptor (AR) inhibitor enzalutamide (ENZ), patients develop resistance to ENZ, posing a serious threat to male health. However, there are currently no effective drugs for treating prostate cancer patients with ENZ resistance. Based on the structural optimization and modification of enzalutamide, and through molecular biological methods such as cell viability assays, colony formation, cell apoptosis detection, Western blot and other molecular biology techniques, it was discovered that the half-maximal inhibitory concentration values of LS-13 for prostate cancer LNCaP-ENZR and 22RV1 cells are 17.09 and 19.90 μmol·L-1, respectively. Subsequently, after treating the resistant cell lines with 0.1, 1, 5, and 10 μmol·L-1 of LS-13 for 12 days, the observation results indicated that LS-13 could inhibit the in vitro clonal formation of LNCaP-ENZR and 22RV1 cells in a dose-dependent manner. Furthermore, after treating the resistant cell lines with 1.25, 2.5, 5, and 10 μmol·L-1 of LS-13 for 72 h, the results of flow cytometry also showed that LS-13 could promote apoptosis of the resistant cell lines in a dose-dependent manner. Furthermore, under the same concentration conditions described above, after LS-13 treatment of 22RV1 cells for 24 h, it was found that their migration speed was significantly slowed down (P < 0.05). These results collectively indicate that the small molecule compound LS-13 has a pronounced effect in inhibiting ENZR. Further mechanism studies found that LS-13 can target ARfl/ARv7 and promote its protein degradation, inhibit the transcription levels of AR-downstream target genes, thereby suppressing ENZR cell proliferation and promoting apoptosis. This study provides a candidate compound for targeting ARfl/ARv7 to overcome ENZ resistance.

prostate cancer  /  drug resistance  /  enzalutamide  /  degradation  /  androgen receptor
韩正义, 梁艳, 曹鹏, 尹震宇, 李岩. 靶向ARfl/ARv7新型小分子降解剂LS-13抑制前列腺癌恩杂鲁胺耐药的药效及机制研究. 药学学报, 2025 , 60 (6) : 1739 -1745 . DOI: 10.16438/j.0513-4870.2025-0061
Zheng-yi HAN, Yan LIANG, Peng CAO, Zhen-yu YIN, Yan LI. The efficacy and mechanism of the novel small molecule degradation agent LS-13 targeting ARfl/ARv7 to inhibit enzalutamide resistant in prostate cancer[J]. Acta Pharmaceutica Sinica, 2025 , 60 (6) : 1739 -1745 . DOI: 10.16438/j.0513-4870.2025-0061
正文
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前列腺癌(prostate cancer, PCa) 是男性癌症中最常见的类型[1]。根据GLOBO CAN的数据显示2022年全球约有150万新发PCa病例和39.7万例死亡[2]。基于对前列腺癌的临床治疗指南的分析发现, 恩杂鲁胺(enzalutamide, ENZ) 仍是目前治疗晚期前列腺癌最为有效的药物[3]。在去势抵抗性前列腺癌(castration-resistant prostate cancer, CRPC) 中, ENZ通过有效抑制雄激素与雄激素受体(androgen receptor, AR) 的结合, 从而阻止AR靶基因的转录[4]。不幸的是, 长期使用ENZ治疗的部分患者最终都会出现耐药的情况[5], 这大大降低了患者的生存率。因此, 解决恩杂鲁胺耐药(enzalutamide resistance, ENZR) 的问题至关重要。抗雄激素治疗耐药是限制晚期前列腺癌治疗的关键所在, 而CRPC通常与AR基因过表达相关[6, 7]。同时, 此前报道ENZ耐药与AR的持续激活密切相关[8]。本研究将AR作为重要靶点开发新型小分子AR抑制剂, 解决前列腺癌ENZ耐药的问题。通过对现有活性药物进行结构优化与改造, 合成一系列小分子化合物, 其中小分子降解剂LS-13[9]可以有效地阻止CRPC的进展, 克服ENZR。通过其体外药效发现LS-13对PCa恩杂鲁胺耐药细胞有一定抑制增殖与促凋亡的作用。这为LS-13抑制前列腺癌ENZ耐药的应用提供了实验依据。
材料与方法
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实验材料   PCa恩杂鲁胺耐药细胞LNCaP和22RV1购自中国科学院细胞库; LS-13由中国药科大学提供; ENZ (HY-70002) 购自美国MedChemExpress公司; 环己酰亚胺(cycloheximide, CHX) (S7418) 购自美国Selleckche公司; 磺酰罗丹明B (sulforhodamine B, SRB) (S1402) 购自美国Sigma公司; 结晶紫(C0121)、RIPA裂解液(中)(P0013C)、Western blot一抗稀释液(P0023A) 均购自上海碧云天生物技术有限公司; ECL (FD8020) 购自杭州弗德生物科技有限公司; RNAiso Plus试剂(9109) 购自日本Takara公司; 引物购自金斯瑞生物科技股份有限公司; HiScript Ⅲ RT SuperMix for qPCR (+gDNA wiper) 试剂(R323-01)、ChamQ Blue Universal SYBR qPCR Master Mix试剂(Q312-02) 均购自南京诺唯赞生物科技股份有限公司; Annexin V-Alexa Flour647/PI细胞凋亡检测试剂盒(BA00103) 购自北京博奥森生物技术有限公司。
抗体ARfl (ab108341) 购自英国Abcam公司; 抗体ARv7 (19672S) 购自美国Cell Signaling Technology公司; 抗体β-actin (20536-1-AP)、HRP-conjugated goat anti-rabbit IgG(H+L) (SA00001-2) 均购自美国Proteintech公司。
全波长多功能酶标仪(美国ThermoFisher公司, Varioskan LUX); 全自动化学发光图像分析系统(上海天能科技有限公司, 5200Multi); PCR扩增仪(美国Scilogex公司, SCI1000-G); 实时荧光定量PCR系统(美国ThermoFisher公司, QuantStudio3); 流式细胞仪(美国Beckman Coulter公司, CytoFLEX S)。
细胞培养   恩杂鲁胺耐药细胞LNCaP-ENZR和22RV1使用添加10%胎牛血清和1%青霉素-链霉素的RPMI-1640培养液, 置于37 ℃、5% CO2的培养箱中培养。
LNCaP-ENZR细胞的构建   ARfl及ARv7过表达是LNCaP-ENZR细胞耐药的特点。其构建方法是在培养到状态良好、对数生长期的LNCaP细胞中每隔一天定量加入10 μmol·L-1 ENZ, 3个月后, 将多克隆ENZR细胞持续暴露在更高浓度的ENZ中, 并最终在含有30 μmol·L-1 ENZ的培养基中维持[10]。
SRB测定细胞活力   取对数生长LNCaP-ENZR和22RV1细胞按4 000个/孔接种在96孔板中培养过夜, 用不同浓度的LS-13处理细胞72 h, 然后用10%三氯乙酸固定。之后用0.4% SRB和1%乙酸对细胞进行染色和洗涤, 其中SRB用100 μL Tris-HCl (10 mmol·L-1) 溶解。最后, 在575 nm波长处测光密度值变化来评估细胞活力。
集落形成实验   将LNCaP-ENZR细胞和22RV1细胞按1×103个/孔接种在6孔板中, 待贴壁后用DMSO、ENZ (10 μmol·L-1) 和LS-13 (0.1、1、5、10 μmol·L-1) 处理12天。实验终点用结晶紫染色, 最后拍照记录。
细胞凋亡实验   以密度3×105个/孔的LNCaP-ENZR和22RV1细胞接种到6孔板中, 培养24 h后, LNCaP-ENZR和22RV1细胞加入DMSO、ENZ (10 μmol·L-1)、LS-13 (1.25、2.5、5、10 μmol·L-1) 孵育72 h后, 收集细胞。根据Annexin V-Alexa Flour647/PI细胞凋亡检测试剂盒说明书进行染色, 上机流式细胞仪检测并分析处理数据。
划痕实验   首先在6孔板背后用marker笔均匀地画3条横线, 取22RV1细胞按照5×105个/孔的密度接种于6孔板中, 当细胞融合率接近100%时, 用白枪头垂直于板背后的横线画3道痕[11]。PBS洗3次后, 加入DMSO、ENZ (10 μmol·L-1)、LS-13 (1.25、2.5、5、10 μmol·L-1), 于0和24 h在倒置显微镜下拍照。
分子对接   将AR-LBD (PDB: 2OZ7) PDB文件从蛋白质数据(http://www.rcsb.org/) 下载, 用Auto dock Vina 1.1.2进行AR-LBD与LS-13分子对接[12]。
Western blot  将22RV1细胞以3×105个/孔接种于6孔板中。次日待细胞贴壁后, 按指定时间和药物浓度给药, 培养到时间后用RIPA裂解液提取细胞总蛋白, 在冰上裂解30 min, 间隔5 min涡旋一次。将提取的细胞蛋白进行Western blot, 凝胶成像仪拍照, 使用Adobe Illustrator处理图片。
实时荧光定量PCR (RT-qPCR)   用RNAiso Plus试剂提取总RNA, 按照HiScript Ⅲ RT SuperMix for qPCR (+gDNA wiper) 试剂的说明书操作将RNA逆转cDNA。然后, 使用2× ChamQ Blue Universal SYBR qPCR Master Mix混合引物进行qPCR (表1)。数据用ΔΔCt方法以相对mRNA (靶基因/β-actin) 表示。
统计学分析   数据采用GraphPad Prism 8进行分析。使用Tukey′s多重比较检验校正的单因素方差分析比较P值。P < 0.05表示差异具有统计学意义。数据以平均标准误(SEM) 表示。
结果
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1　LS-13抑制PCa恩杂鲁胺耐药细胞的活力
为了确定LS-13 (图1A) 对PCa恩杂鲁胺耐药细胞活力的影响, 利用SRB实验考察了LS-13处理细胞后生存率的变化。依次按0.781 25、1.562 5、3.125、6.25、12.5、25、50和100 μmol·L-1给予, 实验结果显示, 随着LS-13浓度的增高, LNCaP-ENZR和22RV1细胞活力逐渐递减(图1B)。通过GraphPad Prism 8计算LS-13对LNCaP-ENZR和22RV1细胞的IC50结果分别为17.09和19.90 μmol·L-1。以上结果表明: LS-13可以剂量依赖性地抑制ENZ耐药细胞株LNCaP-ENZR和22RV1的生长。为了进一步探究LS-13对耐药细胞株体外克隆的作用, 用0.1、1、5、10 μmol·L-1 LS-13处理单克隆耐药细胞株, 12天后观察细胞状态并用结晶紫染色、洗涤、拍照记录。结果显示, LS-13可剂量依赖性地抑制耐药细胞株的体外克隆, 且其对耐药细胞株的抑制作用明显优于ENZ (图1C)。综上所述: LS-13可以抑制耐药细胞株的增殖。
2　LS-13促进PCa恩杂鲁胺耐药细胞的凋亡
前期研究证实, LS-13可以抑制PCa恩杂鲁胺耐药细胞株的活力。进一步地, 本研究用流式细胞术检测LS-13对耐药细胞株LNCaP-ENZR和22RV1细胞的凋亡的影响, 实验结果显示LS-13可呈现剂量依赖性地促进耐药细胞株的凋亡, 综上结果也进一步证实了LS-13对PCa恩杂鲁胺耐药细胞株LNCaP-ENZR和22RV1的抑制作用(图2)。
3　LS-13抑制22RV1细胞的迁移能力
为了进一步评估LS-13对耐药细胞株的抑制作用, 本课题组开展了划痕实验。通过使用不同浓度的LS-13处理22RV1初期划痕的细胞, 并于24 h后观察并记录划痕的愈合情况。同时, 通过Adobe Illustrator作图软件进行划痕宽度的测量。如图3A、B的实验结果显示, 随着LS-13剂量增加, 22RV1细胞的迁移速度逐渐变慢。同时发现LS-13作用24 h后与0 h相比, 细胞密度减少, 细胞之间的间隙变大。其中, 与DMSO组相比, ENZ (10 μmol·L-1)、LS-13 (1.25、2.5、5和10 μmol·L-1) 处理组的划痕宽度逐渐增加, 且LS-13的效果显著优于ENZ。以上实验结果表明: LS-13可以剂量依赖性地抑制22RV1细胞的平面迁移能力。
4　化合物LS-13抑制22RV1细胞的AR表达及降低AR的蛋白稳定性
为进一步探究小分子化合物抑制前列腺癌耐药的具体作用机制, 本研究首先将小分子化合物LS-13与AR蛋白(PDB ID: 2OZ7) 进行分子对接, 对接结果显示, LS-13可以与AR的Met895、Gly708和Arg752形成关键的氢键相互作用(图4A); 为探究LS-13对AR的作用, 通过Western blot检测用浓度5和10 μmol·L-1 LS-13处理22RV1细胞内AR蛋白的表达。与对照组比较, 发现10 μmol·L-1 LS-13可抑制ARfl及ARv7的蛋白表达, 且其效果显著优于10 μmol·L-1 ENZ (图4B~D)。为了进一步探究LS-13对AR蛋白稳定性的影响, 本研究采用了蛋白合成抑制剂CHX (50 μg·mL-1) 及CHX联合LS-13 (10 μmol·L-1) 处理22RV1细胞, 分别在处理0、0.5、1、2、4、8 h后提取总蛋白, 并通过Western blot对ARfl和ARv7的表达进行检测。实验结果显示: 与对照组相比, LS-13可降低22RV1细胞的ARfl和ARv7的蛋白稳定性, 促进其降解(图4E)。综上表明, 化合物LS-13可以靶向AR, 降低AR的稳定性, 促进AR降解, 进而抑制前列腺癌的恶性进展。
5　化合物LS-13抑制AR转录功能, 抑制下游转录调控基因的活性表达
AR作为一个转录因子[13]可以通过转录调控下游的靶基因KLK3 (编码PSA) 和TMPRSS2等进而调控前列腺癌的恶性进展, 为进一步探究LS-13是否可以通过影响AR蛋白表达进而影响AR转录功能, 本研究通过qPCR检测KLK3和TMPRSS2的mRNA水平。实验结果显示, LS-13可剂量依赖性地抑制AR以及下游KLK3和TMPRSS2的转录水平。与对照组相比, 5和10 μmol·L-1 LS-13均对KLK3和TMPRSS2基因转录有一定程度的抑制作用, 且与10 μmol·L-1 ENZ相比, 10 μmol·L-1 LS-13抑制效果更强。以上实验结果均表明, LS-13可有效拮抗AR转录因子的活性, 从而抑制AR及其下游基因KLK3和TMPRSS2的转录功能和其活性表达, 进而抑制前列腺癌的恶性进展(图5A、B)。
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近年来, 临床治疗PCa的策略与相关药物开发取得了重大进展[14]。AR在PCa发生发展中被视为最重要的因素[15]。因此, 针对AR信号通路进行AR抑制剂的开发是治疗PCa的关键所在。其中, 第二代AR抑制剂ENZ在晚期前列腺癌治疗中表现出显著的疗效。然而, ENZ耐药的发生是CRPC患者死亡的一个主要因素[16]。为了抑制ENZ耐药患者临床恶性程度进展, 亟需寻找新的药物来解决耐药问题。此前本课题组研究发现靶向AR降解是治疗ENZ耐药的有效途径[10], 基于前期的理论与实践的基础, 本课题组进一步对现有药物和活性化合物的结构进行改造与优化, 以期获得活性更高的AR小分子降解剂, 为解决前列腺癌ENZ耐药的问题提供有效的策略与候选化合物。
本研究以ENZ为初始母核结构, 通过三元并环策略对结构进行优化改造, 合成小分子化合物LS-13。进一步的细胞活力实验发现LS-13具有较好的抗肿瘤的药理活性, 可显著抑制LNCaP-ENZR和22RV1细胞的增殖, 促进耐药细胞株的凋亡。更值得注意的是, LS-13对PCa恩杂鲁胺耐药细胞生长的抑制作用显著优于ENZ。在基因水平上发现LS-13可显著抑制PCa恩杂鲁胺耐药细胞株AR的表达并抑制其下游调控基因TMPRSS2和KLK3的mRNA水平。Western blot及蛋白稳定性实验结果显示, LS-13联合蛋白合成抑制剂CHX可时间依赖性地降低AR蛋白表达水平, 降低AR蛋白稳定性, 促进其降解。
综上所述, 本研究提出靶向AR降解是治疗ENZ耐药的有效途径, 为ENZR药物开发提供了新的思路与方法。LS-13作为基于第二代AR抑制剂ENZ设计改造而来的新型小分子化合物, 可通过靶向AR, 降低其蛋白稳定性, 加速AR降解, 从而实现逆转前列腺癌ENZ耐药的疗效, 是治疗ENZ耐药的一种潜在小分子降解剂, 可作为临床治疗ENZ耐药的一种候选化合物。

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doi: 10.16438/j.0513-4870.2025-0061
  • 接收时间：2025-01-17
  • 首发时间：2026-09-20
  • 出版时间：2025-06-12
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  • 收稿日期：2025-01-17
  • 修回日期：2025-04-01
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    1南京中医药大学药学院, 江苏 南京 210023
    2南京中医药大学中药制药过程控制与智能制造技术全国重点实验室, 江苏 南京 210023
    3南京中医药大学鼓楼临床医学院, 江苏 南京 210008
    4南京大学医学院附属金陵医院/东部战区总医院, 江苏 南京 210007

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species		 占总种数比例
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total species (%)		 属
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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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