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Article(id=1218263659101474979, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263653049094254, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2017-0506, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1495382400000, receivedDateStr=2017-05-22, revisedDate=1497196800000, revisedDateStr=2017-06-12, acceptedDate=null, acceptedDateStr=null, onlineDate=1768386290574, onlineDateStr=2026-01-14, pubDate=1505404800000, pubDateStr=2017-09-15, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768386290574, onlineIssueDateStr=2026-01-14, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768386290574, creator=13701087609, updateTime=1768386290574, updator=13701087609, issue=Issue{id=1218263653049094254, tenantId=1146029695717560320, journalId=1189982191388893191, year='2017', volume='52', issue='9', pageStart='1351', pageEnd='1484', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768386289131, creator=13701087609, updateTime=1768386664469, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1218265227385295605, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263653049094254, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1218265227385295606, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263653049094254, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1416, endPage=1423, ext={EN=ArticleExt(id=1218263660775002294, articleId=1218263659101474979, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Screening of natural small molecule IDO-1 inhibitors with anti-tumor role, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=ORIGINAL ARTICLES, runingTitle=null, highlight=null, articleAbstract=

Fragments of the human indoleamine 2, 3-dioxygenase 1 (IDO1) gene 5'-UTR (untranslated 1 245 bp region) promoters were amplified by PCR and cloned into pGL4.20 vector in the construction of reporter vector pGL4-IDO1-luc. A549 cells were transfected with the constructed plasmid and IDO1 inhibitor screening model was established with dual-luciferase reporter assay. Based on the model, we screened natural small molecules which could down-regulate the expression of IDO1 on tumor cells. The anti-tumor activities were examined by MTT, Western blotting and lactic dehydrogenase (LDH) release assays. Toosendanin (NS-180) down regulated the IDO1 expression and inhibited IFN-γ-induced STAT1 and STAT3 phosphorylation in A549 cells. Moreover, NS-180 significantly increased the cytotoxicity of co-cultured NK cells on A549 cells in LDH release assays. In summary, NS-180 is a novel and potent IDO1 inhibitor, which has an antitumor activity for cancer immunotherapies.

, correspAuthors=Hong-bin DENG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2017 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, authorCompany=null, fund=null, authors=null, authorsList=Wei-qiang PANG, Lei GAO, Yue-ying DOU, Lu LIU, Na ZHANG, Xiao-jia LIU, Yang LIU, Zhao-yong YANG, Dan-qing SONG, Hong-bin DENG), CN=ArticleExt(id=1218263662964429106, articleId=1218263659101474979, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=IDO1天然小分子抑制剂的筛选及抗肿瘤作用研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

PCR扩增人吲哚胺2，3-双加氧酶1（indoleamine 2，3-dioxygenase 1，IDO1）基因启动子上游区域1 245 bp基因片段，将其插入到pGL4.20-basic载体中构建了pGL4-IDO1-luc荧光素酶重组质粒。基于双荧光素酶报告基因方法建立IDO1抑制剂筛选模型，筛选能够下调肿瘤细胞中IDO1表达的天然活性小分子化合物。采用MTT、Western blotting和乳酸脱氢酶（LDH）等方法探讨阳性化合物的抗肿瘤作用及其对IDO1的调控机制。化合物川楝素（toosendanin，NS-180）能显著下调IFN-γ诱导的肿瘤细胞中IDO1表达。在A549细胞中，NS-180可抑制STAT1和STAT3的磷酸化，从而下调IFN-γ诱导的IDO1蛋白表达。LDH释放实验表明，NS-180可促进NK细胞对A549细胞的杀伤作用。综上所述，筛选获得的天然小分子NS-180是一类新型高效的IDO1抑制剂，可能成为靶向IDO1的肿瘤免疫治疗候选药物。

, correspAuthors=邓洪斌, authorNote=null, correspAuthorsNote=
* 邓洪斌, Tel: 86-10-63169876, Fax: 86-10-63017302, E-mail:
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Pancreatology, 2010, 10:631-640., articleTitle=null, refAbstract=null), Reference(id=1218968468460851952, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[22], rfOrder=21, authorNames=null, journalName=null, refType=null, unstructuredReference=Munn DH. Indoleamine 2, 3-dioxygenase, tumor-induced tolerance and counter-regulation[J]. Curr Opin Immunol, 2006, 18:220-225., articleTitle=null, refAbstract=null), Reference(id=1218968468603458300, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[23], rfOrder=22, authorNames=null, journalName=null, refType=null, unstructuredReference=Liu X, Newton RC, Friedman SM, et al. Indoleamine 2, 3-dioxygenase, an emerging target for anti-cancer therapy[J]. Curr Cancer Drug Targets, 2009, 9:938-952., articleTitle=null, refAbstract=null), Reference(id=1218968468746064648, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[24], rfOrder=23, authorNames=null, journalName=null, refType=null, unstructuredReference=Fallarino F, Grohmann U, Puccetti P. Indoleamine 2, 3-dioxygenase:from catalyst to signaling function[J]. Eur J Immunol, 2012, 42:1932-1937., articleTitle=null, refAbstract=null), Reference(id=1218968468880282387, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[25], rfOrder=24, authorNames=null, journalName=null, refType=null, unstructuredReference=Ju J, Qi Z, Cai X, et al. The apoptotic effects of toosendanin are partially mediated by activation of deoxycytidine kinase in HL-60 cells[J]. PLoS One, 2012, 7:e52536., articleTitle=null, refAbstract=null), Reference(id=1218968469031277343, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[26], rfOrder=25, authorNames=null, journalName=null, refType=null, unstructuredReference=Li X, You M, Liu YJ, et al. Reversal of the apoptotic resistance of non-small-cell lung carcinoma towards TRAIL by natural product toosendanin[J]. 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Jilin Institute for Drug Control, Changchun 130000, China), AuthorCompanyExt(id=1218968457656324730, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, companyId=1218968457631158899, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.吉林省药品检验所, 吉林 长春 130000)])], figs=[ArticleFig(id=1218968463201194145, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=EN, label=null, caption=null, figureFileSmall=rNxephssNNhIs2LPt01F2Q==, figureFileBig=Qcv1eLQEkkFmGHKulOvZxg==, tableContent=null), ArticleFig(id=1218968463377354929, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=CN, label=Figure 1, caption=

Amplification of IDO1-promotor region gene fragments by PCR. M: 2 kb plus marker; 1: IDO1-promotor 1 245 bp. IDO1: Indoleamine 2, 3-dioxygenase 1

, figureFileSmall=rNxephssNNhIs2LPt01F2Q==, figureFileBig=Qcv1eLQEkkFmGHKulOvZxg==, tableContent=null), ArticleFig(id=1218968463519961277, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=EN, label=null, caption=null, figureFileSmall=yz1aN3ITzVbmH5oVScolZg==, figureFileBig=WnETzUXcJlajwBiadRNQWQ==, tableContent=null), ArticleFig(id=1218968463666761931, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=CN, label=Figure 2, caption=

Kpn Ⅰ and Hind Ⅲ double digestion result of recombinant plasmid pGL4-IDO1-luc and pGL4.20-basic. M: 2 kb plus marker; 1: pGL4-IDO1-luc doubled digested by Kpn Ⅰ+Hind Ⅲ; 2: pGL4.20 basic double digested by Kpn Ⅰ+Hind Ⅲ

, figureFileSmall=yz1aN3ITzVbmH5oVScolZg==, figureFileBig=WnETzUXcJlajwBiadRNQWQ==, tableContent=null), ArticleFig(id=1218968463775813850, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=EN, label=null, caption=null, figureFileSmall=fLWakUnaEp/tYXlw+0W6kQ==, figureFileBig=OsVyHOuUIFhDT1/VShoR1w==, tableContent=null), ArticleFig(id=1218968463889060070, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=CN, label=Figure 3, caption=

Sequences analysis of the IDO1 gene 5'-UTR promoter

, figureFileSmall=fLWakUnaEp/tYXlw+0W6kQ==, figureFileBig=OsVyHOuUIFhDT1/VShoR1w==, tableContent=null), ArticleFig(id=1218968464010694898, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=EN, label=null, caption=null, figureFileSmall=1dsslMntb3+iY9er8Peh6Q==, figureFileBig=fqBClwo1RG6p8q8aOCAjtQ==, tableContent=null), ArticleFig(id=1218968464123941121, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=CN, label=Figure 4, caption=

Nucleotide sequence of the promoter region of human IDO1 gene. Nucleotides ranging from -1 236 upstream to 9 downstream of the translation initiation site (ATG) are shown. Transcription factor ISRE, GAS and LEF-1/TCF binding sites are underlined and named below the sequence. GAS: Gamma activation sequences; ISRE: Interferon stimulation reaction element; LEF-1/TCF: Lymphoid enhancer-bind factor 1/T cell factor

, figureFileSmall=1dsslMntb3+iY9er8Peh6Q==, figureFileBig=fqBClwo1RG6p8q8aOCAjtQ==, tableContent=null), ArticleFig(id=1218968464253964560, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=EN, label=null, caption=null, figureFileSmall=9zoe+KLmjA++hOMtGP6I/w==, figureFileBig=66bGFUI2uhqeiOxEUU1RzQ==, tableContent=null), ArticleFig(id=1218968464392376606, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=CN, label=Figure 5, caption=

Functional analyses of IDO1 promoter in A549 cells. IDO1 promoter construct (pGL4-IDO1-luc) and renilla control vector (pRL-TK) were transiently transfected into A549 cells. The luciferase activities were measured in basal conditions, or after stimulation by IFN-γ (5 ng·mL-1). Results are expressed as relative firefly luciferase units normalized to renilla luciferase. n = 3,$\overline{x}±s$. ***P < 0.001 vs the pGL4.20 basic group

, figureFileSmall=9zoe+KLmjA++hOMtGP6I/w==, figureFileBig=66bGFUI2uhqeiOxEUU1RzQ==, tableContent=null), ArticleFig(id=1218968464522400044, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=EN, label=null, caption=null, figureFileSmall=eqRD+gBCGZJV+V6ZLmV5/A==, figureFileBig=8ee9Yu5X/L0Pi7oa0xVQiA==, tableContent=null), ArticleFig(id=1218968464677589309, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=CN, label=Figure 6, caption=

Screening of natural small molecule IDO-1 inhibitors. (A, B) A549 cells were transiently transfected with pGL4.20 basic or pGL4-IDO1-luc reporter construct and the pRL-TK as an internal control, followed by pretreatment with 10 μmol·L-1 of different natural small (NS) molecules or DMSO as control for 2 h. After stimulation by IFN-γ (5 ng·mL-1), the level of luciferase activities were determined as described. n = 3, $\overline{x}±s$. **P < 0.01, ***P < 0.001 vs the DMSO group

, figureFileSmall=eqRD+gBCGZJV+V6ZLmV5/A==, figureFileBig=8ee9Yu5X/L0Pi7oa0xVQiA==, tableContent=null), ArticleFig(id=1218968464807612747, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=EN, label=null, caption=null, figureFileSmall=DB+cljcdpsJIYofuZl79ZQ==, figureFileBig=UOsm2XDMUnhU0z0LWJXgbA==, tableContent=null), ArticleFig(id=1218968464946024793, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=CN, label=Figure 7, caption=

Effects of different compounds on A549 cell viability. A549 cells were treated with 10 μmol·L-1 of different NS molecules for 48 h, and cell toxicity was measured by MTT assay. Control cells were treated with 0.5% (v/v) DMSO. n = 3, $\overline{x}±s$. *P < 0.05, **P < 0.01, ***P < 0.001 vs the DMSO group

, figureFileSmall=DB+cljcdpsJIYofuZl79ZQ==, figureFileBig=UOsm2XDMUnhU0z0LWJXgbA==, tableContent=null), ArticleFig(id=1218968465055076708, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=EN, label=null, caption=null, figureFileSmall=btrSjZMI5GePaLWOt+lArA==, figureFileBig=yOFd9Y6DKcKJY8Gf8opgiQ==, tableContent=null), ArticleFig(id=1218968465151545708, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=CN, label=Figure 8, caption=

NS-180 down-regulates the IFN-γ-induced expression of IDO1 and inhibits STAT1/STAT3 phosphorylation. The chemical structure of NS-180 (A). A549 cells were treated with IFN-γ (5 ng·mL-1) for the indicated times (B), or treated with different concentrations of IFN-γ for 24 h (C), the IDO1 expression level was detected by Western blotting. β-Actin or tubulin served as the loading control. A549 cells were pre-treated with various concentrations of NS-180 for 2 h, followed by IFN-γ (5 ng·mL-1) treatment for 24 h (D). The phosphorylation of STAT1 and STAT3 and expression level of IDO1 were measured by Western blotting using corresponding antibodies. Tubulin served as the loading control

, figureFileSmall=btrSjZMI5GePaLWOt+lArA==, figureFileBig=yOFd9Y6DKcKJY8Gf8opgiQ==, tableContent=null), ArticleFig(id=1218968465252209014, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=EN, label=null, caption=null, figureFileSmall=jghLOVuon/ezCE0A04aR4w==, figureFileBig=nd5ANigkUoBwHyS1a/CD/w==, tableContent=null), ArticleFig(id=1218968465361260933, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263659101474979, language=CN, label=Figure 9, caption=

NS-180 enhances the specific lysis of NK cells to A549 cells. A549 cells were pre-treated with the indicated compounds for 2 h, followed by IFN-γ (5 ng·mL-1) treatment for 24 h. Cells were washed and NK cells were co-cultured with A549 cells at 10:1 in RPMI 1640 plus 10% FBS for 16 h. The specific lysis of NK cells to A549 cells was determined by lactic dehydrogenase (LDH) releasing assay. 1-Methyl-tryptophan (1-MT) was used as the positive control. n = 3, $\overline{x}±s$. **P < 0.01, ***P < 0.001 vs the DMSO group

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IDO1天然小分子抑制剂的筛选及抗肿瘤作用研究
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庞伟强 1 , 高磊 2 , 窦玥莹 1 , 刘璐 1 , 张娜 1 , 刘晓嘉 1 , 刘阳 1 , 杨兆勇 1 , 宋丹青 1 , 邓洪斌 1, *
药学学报 | 研究论文 2017,52(9): 1416-1423
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药学学报 | 研究论文 2017, 52(9): 1416-1423
IDO1天然小分子抑制剂的筛选及抗肿瘤作用研究
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庞伟强1, 高磊2, 窦玥莹1, 刘璐1, 张娜1, 刘晓嘉1, 刘阳1, 杨兆勇1, 宋丹青1, 邓洪斌1, *
作者信息
  • 1.中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050
  • 2.吉林省药品检验所, 吉林 长春 130000

通讯作者:

* 邓洪斌, Tel: 86-10-63169876, Fax: 86-10-63017302, E-mail:
Screening of natural small molecule IDO-1 inhibitors with anti-tumor role
Wei-qiang PANG1, Lei GAO2, Yue-ying DOU1, Lu LIU1, Na ZHANG1, Xiao-jia LIU1, Yang LIU1, Zhao-yong YANG1, Dan-qing SONG1, Hong-bin DENG1, *
Affiliations
  • 1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
  • 2. Jilin Institute for Drug Control, Changchun 130000, China
出版时间: 2017-09-15 doi: 10.16438/j.0513-4870.2017-0506
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摘要
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PCR扩增人吲哚胺2，3-双加氧酶1（indoleamine 2，3-dioxygenase 1，IDO1）基因启动子上游区域1 245 bp基因片段，将其插入到pGL4.20-basic载体中构建了pGL4-IDO1-luc荧光素酶重组质粒。基于双荧光素酶报告基因方法建立IDO1抑制剂筛选模型，筛选能够下调肿瘤细胞中IDO1表达的天然活性小分子化合物。采用MTT、Western blotting和乳酸脱氢酶（LDH）等方法探讨阳性化合物的抗肿瘤作用及其对IDO1的调控机制。化合物川楝素（toosendanin，NS-180）能显著下调IFN-γ诱导的肿瘤细胞中IDO1表达。在A549细胞中，NS-180可抑制STAT1和STAT3的磷酸化，从而下调IFN-γ诱导的IDO1蛋白表达。LDH释放实验表明，NS-180可促进NK细胞对A549细胞的杀伤作用。综上所述，筛选获得的天然小分子NS-180是一类新型高效的IDO1抑制剂，可能成为靶向IDO1的肿瘤免疫治疗候选药物。

吲哚胺2, 3-双加氧酶1  /  启动子  /  荧光素酶  /  川楝素

Fragments of the human indoleamine 2, 3-dioxygenase 1 (IDO1) gene 5'-UTR (untranslated 1 245 bp region) promoters were amplified by PCR and cloned into pGL4.20 vector in the construction of reporter vector pGL4-IDO1-luc. A549 cells were transfected with the constructed plasmid and IDO1 inhibitor screening model was established with dual-luciferase reporter assay. Based on the model, we screened natural small molecules which could down-regulate the expression of IDO1 on tumor cells. The anti-tumor activities were examined by MTT, Western blotting and lactic dehydrogenase (LDH) release assays. Toosendanin (NS-180) down regulated the IDO1 expression and inhibited IFN-γ-induced STAT1 and STAT3 phosphorylation in A549 cells. Moreover, NS-180 significantly increased the cytotoxicity of co-cultured NK cells on A549 cells in LDH release assays. In summary, NS-180 is a novel and potent IDO1 inhibitor, which has an antitumor activity for cancer immunotherapies.

indoleamine 2, 3-dioxygenase 1  /  promoter  /  luciferase  /  toosendanin
庞伟强, 高磊, 窦玥莹, 刘璐, 张娜, 刘晓嘉, 刘阳, 杨兆勇, 宋丹青, 邓洪斌. IDO1天然小分子抑制剂的筛选及抗肿瘤作用研究. 药学学报, 2017 , 52 (9) : 1416 -1423 . DOI: 10.16438/j.0513-4870.2017-0506
Wei-qiang PANG, Lei GAO, Yue-ying DOU, Lu LIU, Na ZHANG, Xiao-jia LIU, Yang LIU, Zhao-yong YANG, Dan-qing SONG, Hong-bin DENG. Screening of natural small molecule IDO-1 inhibitors with anti-tumor role[J]. Acta Pharmaceutica Sinica, 2017 , 52 (9) : 1416 -1423 . DOI: 10.16438/j.0513-4870.2017-0506
正文
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目前, 恶性肿瘤的诊疗仍是医学界最大的挑战之一, 而传统的恶性肿瘤治疗手段如化疗和放疗等, 虽经不断发展, 却仍存在一定的局限和弊端, 如不良反应大及易诱导耐药等。近年来, 随着肿瘤免疫相关研究的不断深入, 免疫治疗成为改善恶性肿瘤患者预后的新希望。肿瘤与宿主免疫系统之间的相互作用复杂而多变[1]。科学家们正试图阐明两者之间的作用机制, 希望借此改善肿瘤治疗现状。相应的, 肿瘤免疫疗法已成为制药工业的热门研究领域。
作为众多肿瘤免疫周期调节因子中的一员, 吲哚胺2, 3-双加氧酶1 (indoleamine 2, 3-dioxygenase 1, IDO1) 备受关注[2,3]。IDO1是色氨酸分解代谢的第一限速酶, 可通过介导色氨酸的耗竭及其代谢产物犬尿氨酸的积累来诱导T细胞和NK细胞的凋亡或功能紊乱, 从而减弱机体的抗肿瘤免疫[4-7]。在多数组织中, IDO1处于沉默状态, 但在多种实体肿瘤如肺癌、肝癌、乳腺癌和结肠癌等肿瘤组织中则呈持续高表达状态, 且与预后差密切相关[8]。研究表明, IDO1活性的抑制可以促进免疫接种及化学治疗的疗效, 使得IDO1成为肿瘤免疫治疗药物的一个重要靶标。近年来, 抑制IDO1的活性在肿瘤治疗中的作用引起了众多学者的关注[9]。因此, 筛选高效的IDO1抑制剂, 激活T细胞和NK细胞的功能, 打破肿瘤免疫耐受, 可能为肿瘤免疫治疗带来新的突破。
根据IDO1的调节及效应机制, 以IDO1为靶点的治疗可通过抑制IDO1基因表达、抑制IDO1活性及阻滞其效应途径, 发挥治疗的作用。目前国内外研究开发的以IDO1为靶点的小分子抑制剂主要集中在以直接抑制IDO1活性方面的研究, 如1-甲基-色氨酸(1-methyl-tryptophan, 1-MT)、NLG919和INCB024360等[10]。但是它们普遍存在抑制效率低下、无法透过细胞膜及产生吲哚环结构代谢物质等问题[11]。
本研究拟构建包含人的IDO1启动子片段的荧光素酶报告基因载体, 建立IDO1抑制剂筛选模型, 并从天然小分子化合物库中筛选新型高效的能够下调IDO1表达的活性化合物。此外, 还对筛选出的阳性化合物的抗肿瘤作用及其对IDO1的调控机制进行初步研究。
材料与方法
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主要试剂及材料
DMEM、DMEM/F12、RPMI 1640培养基和胎牛血清购自美国Hyclone公司; 胰蛋白酶(trypsin)、3-(4, 5-二甲基噻唑-2)-2, 5-二苯基四氮唑溴盐(MTT)、青霉素/链霉素溶液、琼脂糖和溴化乙锭(EB)购自美国Sigma公司; 1-MT购自美国Selleck公司; 丙烯酰胺、甲叉双丙烯酰胺、十二烷基磺酸钠(SDS)、Tris碱、过硫酸铵及Tween-20均购自美国Amresco公司; PVDF膜购自美国Millipore公司; ECL Plus超敏免疫印迹检测试剂盒购自美国Amersham Pharmacia公司; 一抗IDO、STAT3、STAT1、phospho-STAT3 (Ser727)、phospho-STAT1 (Tyr701)、phospho-ACC (Ser79)、α-tubulin、β-actin和羊抗兔或小鼠二抗均购自美国Cell Signaling公司; Prime STAR HS DNA Polymerase、Kpn Ⅰ、Hind Ⅲ、T4 ligase酶、广谱型基因组DNA小量纯化试剂盒、DNA凝胶回收试剂盒和DNA片段纯化试剂盒均购自大连宝生物公司; 高纯度质粒小提中量试剂盒购自北京天根生化科技有限公司; VigoFect转染试剂购自北京威格拉斯生物技术有限公司; Dual-Luciferase Reporter Assay System kit试剂盒和CytoTox 96® Non-Radioactive Cytotoxicity试剂盒购自美国Promega公司; 天然小分子化合物库购自上海诗丹得生物技术有限公司。
仪器  Berthold LB942荧光检测仪为德国伯托公司产品; Tanon-5100凝胶成像系统为上海天能公司产品; Multiskan FC型酶标仪为赛默飞世尔(上海)仪器有限公司产品。
细胞系和质粒  人正常肝细胞L02、人非小细胞肺癌A549细胞由本实验室保存; 人NK细胞由中国医学科学院医药生物技术研究所杨兆勇教授课题组提供; pGL4.20-basic质粒和pRL-TK质粒购自美国Promega公司。
人 IDO1 启动子报告基因载体的构建
PCR反应模板的制备  收集人正常肝细胞L02, 裂解后参照TaKaRa公司的广谱型基因组DNA小量纯化试剂盒的使用说明, 进行全基因组DNA的提取, 制备应用于PCR反应的模板, -80 ℃保存。
引物的设计与合成  根据IDO1基因启动子的序列(GenBank：JN382541.1) 并且参考Konan等[12]的实验方案设计PCR引物。引物由上海生工公司合成, 在合成的引物序列中导入了KpnⅠ和Hind Ⅲ内切酶酶切位点(斜体部分), 供后续酶切鉴定用。上游和下游引物分别为: 5'-ggggtaccGATTCCCAAAGTAT TAGC-3'; 5'-ccaagcttTCTTGTAGTCTGCTCCTC-3'。
IDO1启动子基因的克隆  以试剂盒提取的L02细胞全基因组DNA为模板, 用上述设计引物进行PCR扩增, PCR反应条件为98 ℃预变性30 s; 98 ℃变性10 s, 55 ℃复性15 s, 72 ℃延伸2 min 12 s, 循环3次; 98 ℃变性10 s, 58 ℃复性15 s, 72 ℃延伸2 min 12 s, 循环27次; 最后72 ℃再延伸20 min。用10 g·L-1琼脂糖凝胶进行电泳。参照TaKaRa公司的胶回收试剂盒操作说明, 回收并纯化1 245 bp PCR产物。
质粒的构建及鉴定  回收PCR产物, 用Kpn Ⅰ和Hind Ⅲ双酶切IDO1启动子基因的PCR产物和pGL4.20-basic载体, 回收PCR产物和载体大片段, 用T4连接酶25 ℃连接4 h后, 将连接产物转化DH5α感受态细菌并涂平板。挑取单克隆接入5 mL带Amp抗性的LB培养基中, 用高纯度质粒小提中量试剂盒提取菌液中质粒。经Kpn Ⅰ和Hind Ⅲ双酶切鉴定后送上海生工公司测序, 将测序正确的重组质粒命名为pGL4-IDO1-luc。
含 IDO1 启动子报告基因载体的活性检测
细胞培养  转染24 h前, 采用0.25%胰酶消化, 利用含10%胎牛血清的DMEM/F12培养基将处于对数生长期的细胞制备成单细胞悬液, 按1×105个/孔接种至24孔板中, 每孔培养基为500 μL, 置37 ℃、5% CO2饱和湿度培养箱培养, 待细胞生长至铺满孔底70%左右进行实验。
瞬时转染与加药处理  用150 mmol·L-1 NaCl稀释待转染的质粒, pGL4.20-basic载体、pGL4-IDO1-luc均按每孔400 ng的量, pRL-TK按每孔20 ng的量, 以每孔50 μL体积稀释质粒, 轻轻混匀, 每个质粒做3个复孔。参照VigoFect转染试剂说明, 在A549细胞中进行pGL4-IDO1-luc/pRL-TK共转染, 同时设立pGL4.20-basic/pRL-TK共转染作为阴性对照组。细胞在37 ℃培养24 h后, 弃去培养液, 根据实验需要加入相应的药物处理(如IFN-γ), 继续培养24 h, 检测荧光素酶活性。
双荧光素酶报告基因活性的检测  参照试剂盒说明书测定荧光素酶活性。去除培养孔中的培养液, 用1×PBS (pH 7.4) 清洗2次; 每孔加被动裂解缓冲液PLB 100 μL, 室温振摇15 min; 每孔裂解产物取上清20 μL转移至96孔板中; 使用荧光素酶检测试剂Ⅱ (LAR Ⅱ)和Stop & Glo®试剂进行目的报告基因荧火虫荧光素酶(firefly luc)及内参海肾素荧光素酶(renilla luc)检测, 计算荧火虫荧光素酶与海肾素荧光素酶的比值, 并以空载体pGL4.20-basic和pRL-TK共转染细胞作为对照。实验数据采用GraphPad prism 5软件进行统计学分析。
MTT法检测A549细胞增殖的变化  取对数生长期A549细胞制备单细胞悬液, 以6×103个/孔密度接种于96孔板, 每组设置3个复孔, 同时设空白对照(仅加培养液)。待细胞密度达到50%左右, 加入相应的药物作用48 h后, 每孔加入5 mg·mL-1 MTT溶液20 μL, 继续培养4 h。每孔加入DMSO 150 μL, 振荡10 min, 使紫色结晶充分溶解, 酶标仪检测各孔吸光度(A570)值。
Western blotting   将用药物处理或未处理的细胞用细胞刮刀刮下, 1 200 ×g离心收集细胞。加入适量裂解液(50 mmol·L-1 Tris-HCl pH 7.5、1% Triton-100、150 mmol·L-1 NaCl、2 mmol·L-1 EDTA、1 mmol·L-1钒酸钠、50 mmol·L-1 NaF、1 mmol·L-1 PMSF、1 mg·mL-1 aprotinin和1 mmol·L-1 leupeptin), 冰浴30 min, 然后14 000 ×g离心15 min, 收集上清液即为蛋白提取液。用标准Bradford方法测定样品的蛋白浓度。于12% SDS聚丙烯酰胺凝胶电泳分离蛋白, 半干法将蛋白转至PVDF膜。转膜结束后, 将其放入含5%脱脂奶粉的TBST (20 mmol·L-1 Tris-HCl、150 mmol·L-1 NaCl和0.1% Tween-20, pH 7.6) 中振荡封闭1 h。封闭后的膜装入杂交袋与一抗溶液(1:1 000稀释) 4 ℃孵育过夜, 用TBST洗膜3次, 以洗去未结合的一抗。与辣根过氧化物酶标记的二抗溶液(抗兔二抗1:2 000稀释、抗鼠二抗1:5 000稀释)在室温孵育1~2 h后, TBST洗膜3次, 按照ECL Plus免疫试剂盒说明书进行显色, 通过Tanon-5100凝胶成像系统捕获并分析图像。
细胞共培养与乳酸脱氢酶(LDH)释放实验  将A549细胞消化后传代于96孔板中, 待细胞完全贴壁后弃原培养液。分别加入DMSO、NS-180和1-MT等药物预处理2 h后, 再加入5 ng·mL-1 IFN-γ刺激24 h。细胞孵育24 h后更换新鲜培养基, 按照NK细胞:A549细胞=10:1的比例向每孔加入NK细胞, 细胞共培养16 h, 取上清, 按照CytoTox 96® Non-Radioactive Cytotoxicity试剂盒说明检测LDH酶活性。同时设立空白组(只有A549细胞, 不加NK细胞)作为自然释放组, 用1.0% NP40溶液裂解细胞作最大释放组。
LDH杀伤率(%) = (LDH实验孔 -LDH自然释放孔) / (LDH最大释放孔 - LDH自然释放孔) × 100
数据统计与处理  每组实验重复3次, 实验数据以$\overline{x}±s$表示, 组间比较采用t检验, P < 0.05具有显著性差异。
结果
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1 人IDO1启动子基因片段的PCR结果
以提取的人正常L02细胞基因组为模板, 进行PCR, 扩增产物经1%琼脂糖凝胶电泳后, 在约1 245 bp处呈现特异性目的条带, 与预计相符, 表明已获得IDO1启动子区基因片段(图 1)。
2 含IDO1启动子区基因质粒的酶切鉴定
重组质粒pGL4-IDO1-luc经限制性内切酶Kpn Ⅰ和Hind Ⅲ双酶切后电泳, 得到与对应目的基因大小相符(约1 245 bp)的条带, 另外还有一条约5 000 bp的线性空载体条带(图 2)。而pGL4.20-basic空载体经双酶切后仅有一条线性条带, 这表明已成功构建重组质粒pGL4-IDO1-luc。
3 含IDO1启动子基因片段的测序鉴定
对重组pGL4-IDO1-luc质粒的插入片段进行测序, 结果表明各酶切位点正确, 经比对后证实测序序列与GeneBank中报道的IDO1启动子区序列相符。选取pGL4-IDO1-luc测序的部分截图(图 3), 下划线序列为上游引物, 表明重组质粒pGL4-IDO1-luc构建成功。对测序得到的IDO1启动子区进行序列分析发现, 该启动子区含有干扰素刺激反应元件1/2 (interferon stimulation reaction element 1/2, ISRE-1/2)、干扰素γ激活序列1/2 (gamma activation sequences 1/2, GAS1/2) 及淋巴增强子结合因子1/T细胞因子(lymphoid enhancer-bind factor 1/T cell factor, LEF-1/ TCF)等多个转录因子结合位点(图 4), 与文献报道一致[13]。
4 重组质粒pGL4-IDO1-luc的活性鉴定
利用VigoFect转染试剂将构建好的重组质粒pGL4-IDO1-luc、空白对照质粒pGL4.20 basic和内参质粒pRL-TK按5:1的比例共转至A549细胞中, 分别加入或不加IFN-γ (5 ng·mL-1)刺激24 h后, 检测荧光素酶的表达情况。结果显示, IFN-γ能显著增强pGL4-IDO1-luc荧光素酶的表达活性, 但并不影响空白质粒的荧光素酶活性(图 5), 说明已成功构建了具有生物活性的IDO1启动子重组质粒pGL4-IDO1-luc。
5 IDO1抑制剂的筛选
将pGL4-IDO1-luc与内参质粒pRL-TK共转染入A549细胞, 24 h后加入终浓度为10 μmol·L-1的NS系列不同天然小分子化合物处理2 h之后, 再加入IFN-γ (5 ng·mL-1)刺激24 h, 分别检测IDO1启动子荧光素酶的活性, 筛选能抑制IDO1基因表达的NS系列化合物。结果显示, 化合物NS-101、NS-122、NS-123、NS-126、NS-137、NS-159、NS-180、NS-195、NS-197、NS-198、NS-203和NS-212等12种化合物能显著抑制IDO1启动子荧光素酶的活性(图 6A,B)。
进一步用MTT法检测上述12种化合物对A549细胞增殖的影响, 以排除细胞毒性化合物。结果发现, NS-180 (川楝素)对A549细胞增殖的抑制作用最弱(图 7)。荧光素酶和MTT结果共同表明, NS-180可显著抑制IDO1启动子活性且对A549细胞的毒性最小, 因此本研究以NS-180为目标化合物, 对其调控IDO1表达进行下一步的研究。NS-180的化学结构如(图 8A)所示。
6 NS-180抑制IFN-γ诱导的IDO1表达和STAT1、STAT3的磷酸化
使用不同浓度的IFN-γ刺激A549细胞24 h, 或5 ng·mL-1 IFN-γ刺激A549细胞不同时间, 采用Western blotting对IDO1蛋白水平进行分析, 结果表明IFN-γ可诱导A549细胞中IDO1的高表达并且具有时间依赖性和剂量依赖性(图 8B,C)。在A549细胞中, 使用不同浓度的NS-180处理2 h后, 再加入5 ng·mL-1 IFN-γ刺激24 h, Western blotting法检测发现NS-180可抑制IFN-γ诱导的IDO1表达(图 8D)。研究表明, 转录激活因子(signal transducer and activator of transcription, STAT)可在转录水平调控IDO1的表达[14-20]。为了证实NS-180是否通过影响STAT活性在转录水平抑制IFN-γ诱导的IDO1表达, 本研究分析了NS-180对IFN-γ诱导的STAT1和STAT3磷酸化的影响。Western blotting结果表明, NS-180能显著抑制STAT1、STAT3的磷酸化, 并抑制IFN-γ诱导的IDO1的表达(图 8D)。
7 NS-180可增强NK细胞对A549细胞的杀伤作用
根据文献[4-7]报道, 肿瘤细胞中高表达的IDO1可抑制NK细胞的增殖并且影响NK细胞的免疫功能。为探讨NS-180抑制肿瘤细胞中IDO1表达后的生物学效果, 以IDO1抑制剂1-MT作为阳性对照, 通过LDH释放法, 在体外进行NK细胞和A549细胞的共培养实验。结果表明, 与对照组相比, NS-180可增强NK细胞对A549细胞的杀伤作用(图 9), 其效果要优于1-MT。
讨论
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基于IDO1在肿瘤发生发展和肿瘤免疫耐受过程中的重要作用, IDO1已被证实是抑制恶性肿瘤形成和提高免疫治疗效果的重要靶点[21-23]。IDO1抑制剂作为肿瘤免疫治疗的潜在药物具有十分广阔的开发前景。
IDO1抑制剂主要分为以下几类：竞争性抑制剂, 如1-MT; 非竞争性抑制剂, 如苯基咪唑; 反竞争性抑制剂, 如生物碱; 通过其他作用的抑制剂等。目前IDO1抑制剂的相关报道已经有很多, 但只有部分抑制剂如1-MT和INCB024360等进入了临床研究阶段, 目前还没有IDO1抑制类的药物上市。对于临床研究中的1-MT, 由于其抑制浓度较高, 使得1-MT在使用时需要的剂量较大, 药物成本是不可忽视的问题。而对于INCB024360, 其药物分子代谢快, 具有不稳定性。同时, 根据目前临床试验的结果, 单纯抑制IDO1活性仅能产生有限的治疗效果, 而在与传统的化学治疗、疫苗治疗等联用时则显著增强了抗肿瘤反应, IDO1在肿瘤进展中的复杂作用不是十分清楚。基于以上分析, IDO1及其抑制剂仍有较大发展空间和研究前景。
本研究构建了含有人IDO1启动子的荧光素酶报告基因的载体pGL4-IDO1-luc并且基于双荧光素酶报告基因系统, 建立了IDO1抑制剂筛选模型。从天然活性小分子化合物库中筛选能够下调IDO1表达的抑制剂, 发现12种阳性化合物能显著抑制IDO1启动子荧光素酶的活性。以抑制活性好、细胞毒性低的NS-180 (川楝素)为目标化合物进行初步机制研究。
STAT1/3作为调节受IFN-γ诱导的IDO1表达的重要转录因子, 它由IFN-γ受体胞质尾区的JAK激酶激活, 发生同源二聚化并转运至核内, 然后结合GAS序列, 直接激活IDO和IRF-1基因的转录表达。另外, STAT1也能通过诱导IRF-1的表达, 使之结合IDO基因调节区的ISRE-1和ISRE-2元件, 从而间接地激活IDO1基因的转录表达[24]。本研究的初步机制研究发现, NS-180可抑制STAT1、STAT3的磷酸化, 从而下调IFN-γ诱导的IDO1表达。此外, NS-180还可增强NK细胞对A549细胞的杀伤作用, 表明NS-180可能是靶向下调IDO1的肿瘤免疫治疗候选药物, 但在动物体内的抗肿瘤效果还有待进一步验证。
川楝素是一种从传统的驱蛔中药楝科植物川楝的树皮或种子中分离得到的四环三萜类化合物, 具有驱蛔、杀虫、抗肉毒效应、抑制神经递质释放和抗肿瘤[25,26]等多种生物活性, 但川楝素能下调肿瘤细胞中IDO1的表达还是首次被发现。近年来, 川楝素的抗肿瘤作用受到了越来越广泛的关注, 研究者对多种人类肿瘤细胞进行了体外实验和体内实验, 但其作用机制尚不明确。川楝素因来源广(川楝子、川楝素和苦楝树等)且生物活性多样, 尤其在人类对恶性肿瘤无法攻克时, 川楝素可作为新型抗肿瘤药物的候选者之一, 具有广阔的发展前景。
本研究发现NS-180是一类新型高效的IDO1抑制剂, 在体外对人非小细胞肺癌A549细胞可下调IFN-γ诱导的IDO1表达并且抑制STAT1、STAT3的磷酸化。通过使用川楝素来下调IDO1的表达, 逆转由IDO1介导的肿瘤细胞免疫耐受, 从而控制肿瘤细胞的生长, 可能成为防治恶性肿瘤的有效方法, 也可能成为川楝素的一种新的抗肿瘤机制。
基金
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  • 国家自然科学基金面上资助项目(81473248)
  • 中国医学科学院重大协同创新项目-重大前沿研究(2016-12M-1-011)
文献
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2017年第52卷第9期
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doi: 10.16438/j.0513-4870.2017-0506
  • 接收时间：2017-05-22
  • 首发时间：2026-01-14
  • 出版时间：2017-09-15
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  • 收稿日期：2017-05-22
  • 修回日期：2017-06-12
基金
国家自然科学基金面上资助项目(81473248)
中国医学科学院重大协同创新项目-重大前沿研究(2016-12M-1-011)
作者信息
    1.中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050
    2.吉林省药品检验所, 吉林 长春 130000

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* 邓洪斌, Tel: 86-10-63169876, Fax: 86-10-63017302, E-mail:
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
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