Development of a novel oncolytic adenovirus controlled by CDX2 promoter for esophageal adenocarcinoma therapy.

IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Journal of Gastroenterology Pub Date : 2024-11-01 Epub Date: 2024-09-04 DOI:10.1007/s00535-024-02147-2
Naohiko Nakamura, Shuhei Shinoda, Mizuho Sato-Dahlman, Brett Roach, Kari Jacobsen, Masato Yamamoto
{"title":"Development of a novel oncolytic adenovirus controlled by CDX2 promoter for esophageal adenocarcinoma therapy.","authors":"Naohiko Nakamura, Shuhei Shinoda, Mizuho Sato-Dahlman, Brett Roach, Kari Jacobsen, Masato Yamamoto","doi":"10.1007/s00535-024-02147-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Prognosis of esophageal adenocarcinoma (EAC) is still poor. Therefore, the development of novel therapeutic modalities is necessary to improve therapeutic outcomes in EAC. Here, we report a novel promoter-controlled oncolytic adenovirus targeting CDX2 (Ad5/3-pCDX2) and its specific anticancer effect for EAC.</p><p><strong>Methods: </strong>We used OE19, OE33, HT29, MKN28, RH30, and HEL299 cell lines. To establish CDX2 overexpressing OE19 cells, pCMV-GLI1 plasmid was transfected to OE19 (OE19 + GLI1). The virus replication and cytocidal effect of replication competent Ad5/3-pCDX2 were analyzed in vitro. Antitumor effect of Ad5/3-pCDX2 was assessed in xenograft mouse models by intratumoral injection of the viruses. Finally, efficacy of combination therapy with Ad5/3-pCDX2 and 5FU was evaluated.</p><p><strong>Results: </strong>EAC cells and HT29 showed high mRNA levels of CDX2, but not MKN28, RH30, and HEL299. We confirmed that deoxycholic acid (DCA) exposure enhanced CDX2 expression in EAC cells and OE19 + GLI1 had persistent CDX2 overexpression without DCA. Ad5/3-pCDX2 showed stronger cytocidal effect in OE19 + GLI1 than OE19, whereas Ad5/3-pCDX2 did not kill CDX2-negative cells. Ad5/3-pCDX2 was significantly replicated in EAC cells and the virus replication was higher in OE19 + GLI1 and OE19 with DCA compared to OE19 without DCA exposure. In vivo, Ad5/3-pCDX2 significantly suppressed OE19 tumor growth and the antitumor effect was enhanced in OE19 + GLI1 tumor. In contrast, Ad5/3-pCDX2 did not show significant antitumor effect in MKN28 tumor. Moreover, Ad5/3-pCDX2 significantly increased the efficacy of 5FU in vitro and in vivo.</p><p><strong>Conclusions: </strong>Ad5/3-pCDX2 showed specific anticancer effect for EAC, which was enhanced by bile acid exposure. Ad5/3-pCDX2 has promising potential for EAC therapy in the clinical setting.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":null,"pages":null},"PeriodicalIF":6.9000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495994/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Gastroenterology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00535-024-02147-2","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/4 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Prognosis of esophageal adenocarcinoma (EAC) is still poor. Therefore, the development of novel therapeutic modalities is necessary to improve therapeutic outcomes in EAC. Here, we report a novel promoter-controlled oncolytic adenovirus targeting CDX2 (Ad5/3-pCDX2) and its specific anticancer effect for EAC.

Methods: We used OE19, OE33, HT29, MKN28, RH30, and HEL299 cell lines. To establish CDX2 overexpressing OE19 cells, pCMV-GLI1 plasmid was transfected to OE19 (OE19 + GLI1). The virus replication and cytocidal effect of replication competent Ad5/3-pCDX2 were analyzed in vitro. Antitumor effect of Ad5/3-pCDX2 was assessed in xenograft mouse models by intratumoral injection of the viruses. Finally, efficacy of combination therapy with Ad5/3-pCDX2 and 5FU was evaluated.

Results: EAC cells and HT29 showed high mRNA levels of CDX2, but not MKN28, RH30, and HEL299. We confirmed that deoxycholic acid (DCA) exposure enhanced CDX2 expression in EAC cells and OE19 + GLI1 had persistent CDX2 overexpression without DCA. Ad5/3-pCDX2 showed stronger cytocidal effect in OE19 + GLI1 than OE19, whereas Ad5/3-pCDX2 did not kill CDX2-negative cells. Ad5/3-pCDX2 was significantly replicated in EAC cells and the virus replication was higher in OE19 + GLI1 and OE19 with DCA compared to OE19 without DCA exposure. In vivo, Ad5/3-pCDX2 significantly suppressed OE19 tumor growth and the antitumor effect was enhanced in OE19 + GLI1 tumor. In contrast, Ad5/3-pCDX2 did not show significant antitumor effect in MKN28 tumor. Moreover, Ad5/3-pCDX2 significantly increased the efficacy of 5FU in vitro and in vivo.

Conclusions: Ad5/3-pCDX2 showed specific anticancer effect for EAC, which was enhanced by bile acid exposure. Ad5/3-pCDX2 has promising potential for EAC therapy in the clinical setting.

Abstract Image

开发由 CDX2 启动子控制的新型溶瘤腺病毒,用于食管腺癌治疗。
背景:食管腺癌(EAC)的预后仍然很差。因此,有必要开发新型治疗方法以改善 EAC 的治疗效果。在此,我们报告了一种新型启动子控制的靶向 CDX2 的溶瘤腺病毒(Ad5/3-pCDX2)及其对 EAC 的特异性抗癌效果:我们使用了OE19、OE33、HT29、MKN28、RH30和HEL299细胞系。为了建立CDX2过表达的OE19细胞,将pCMV-GLI1质粒转染至OE19(OE19 + GLI1)。体外分析了具有复制能力的 Ad5/3-pCDX2 的病毒复制和杀细胞作用。在异种移植小鼠模型中,通过瘤内注射病毒评估了 Ad5/3-pCDX2 的抗肿瘤效果。最后,评估了 Ad5/3-pCDX2 和 5FU 联合疗法的疗效:结果:EAC细胞和HT29显示出较高的CDX2 mRNA水平,而MKN28、RH30和HEL299则没有。我们证实,暴露于脱氧胆酸(DCA)会增强 CDX2 在 EAC 细胞中的表达,而 OE19 + GLI1 在不暴露于 DCA 的情况下也会出现持续的 CDX2 过表达。Ad5/3-pCDX2 在 OE19 + GLI1 中比在 OE19 中显示出更强的杀细胞作用,而 Ad5/3-pCDX2 对 CDX2 阴性细胞没有杀伤作用。Ad5/3-pCDX2 在 EAC 细胞中明显复制,与未暴露于 DCA 的 OE19 相比,在 OE19 + GLI1 和暴露于 DCA 的 OE19 中病毒复制率更高。在体内,Ad5/3-pCDX2 能明显抑制 OE19 肿瘤的生长,在 OE19 + GLI1 肿瘤中的抗肿瘤作用增强。相比之下,Ad5/3-pCDX2 对 MKN28 肿瘤的抗肿瘤作用不明显。此外,Ad5/3-pCDX2还能显著提高5FU在体外和体内的疗效:结论:Ad5/3-pCDX2对EAC有特异性抗癌作用,胆汁酸暴露增强了这种作用。Ad5/3-pCDX2在EAC临床治疗中具有广阔的前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of Gastroenterology
Journal of Gastroenterology 医学-胃肠肝病学
CiteScore
12.20
自引率
1.60%
发文量
99
审稿时长
4-8 weeks
期刊介绍: The Journal of Gastroenterology, which is the official publication of the Japanese Society of Gastroenterology, publishes Original Articles (Alimentary Tract/Liver, Pancreas, and Biliary Tract), Review Articles, Letters to the Editors and other articles on all aspects of the field of gastroenterology. Significant contributions relating to basic research, theory, and practice are welcomed. These publications are designed to disseminate knowledge in this field to a worldwide audience, and accordingly, its editorial board has an international membership.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信