The Synergistic Anti-Tumor Activity of EZH2 Inhibitor SHR2554 and HDAC Inhibitor Chidamide through ORC1 Reduction of DNA Replication Process in Diffuse Large B Cell Lymphoma
| العنوان: | The Synergistic Anti-Tumor Activity of EZH2 Inhibitor SHR2554 and HDAC Inhibitor Chidamide through ORC1 Reduction of DNA Replication Process in Diffuse Large B Cell Lymphoma |
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| المؤلفون: | Zhitao Ying, Lijuan Deng, Hui Yu, Feier Feng, Jun Zhu, Luni Hu, Jiao Li, Lan Mi, Dedao Wang, Wei Fang, Chao Zhong, Meng Wu, Xing Wang, Yime Zhang, Yunfei Shi, Yuqin Song, Yingying Ye, Ning Ding |
| المصدر: | Cancers, Vol 13, Iss 4249, p 4249 (2021) Cancers Volume 13 Issue 17 |
| بيانات النشر: | MDPI AG, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, Cell growth, EZH2 inhibitor, diffuse large B-cell lymphoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, macromolecular substances, Cell cycle, medicine.disease, Article, chemistry.chemical_compound, Oncology, chemistry, In vivo, Apoptosis, Chidamide, Cancer research, medicine, Viability assay, Histone deacetylase, synergistic effects, DNA replication process, Diffuse large B-cell lymphoma, RC254-282 |
| الوصف: | Simple Summary The EZH2-targeted drugs have demonstrated notable therapeutic effects in EZH2 mutant B-cell lymphoma patients. In this study, we demonstrated that the combination of EZH2 inhibitor SHR2554 and HDAC inhibitor HBI8000 exert synergistic anti-proliferative activity in both EZH2 wide-type and mutation B-cell lymphoma. More importantly, gene expression profile analysis revealed simultaneous treatment with these agents led to dramatic inhibition of DNA replication initiator protein ORC1, which might contribute to great efficacy of combination strategy. The combination of EZH2 inhibitor and HDAC inhibitor could provide a potential therapeutic treatment for both EZH2 wide-type and mutation B-cell lymphoma patients. Abstract Background: Upregulation of H3K27me3 induced by EZH2 overexpression or somatic heterozygous mutations were implicated in lymphomagenesis. It has been demonstrated that several EZH2-target agents have notable therapeutic effects in EZH2-mutant B-cell lymphoma patients. Here we present a novel highly selective EZH2 inhibitor SHR2554 and possible combination strategy in diffuse large B-cell lymphoma (DLBCL). Methods: Cell proliferation, cell cycle and apoptosis were analyzed by CellTiter-Glo Luminescent Cell Viability Assay and flow cytometry. Western Blot was used to detect the expression of related proteins. The gene expression profiling post combination treatment was analyzed by RNA-Seq. Finally, CDX and PDX models were used to evaluate the synergistic anti-tumor effects of the combination treatment in vivo. Results: The novel EZH2 inhibitor SHR2554 inhibited proliferation and induced G1 phase arrest in EZH2-mutant DLBCL cell lines. The combination of EZH2 inhibitor SHR2554 with histone deacetylase (HDAC) inhibitor chidamide (hereafter referred to as HBI8000) exerted synergistic anti-proliferative activity in vitro and in vivo. Gene expression profile analysis revealed dramatic inhibition of the DNA replication process in combined treatment. Conclusions: SHR2554, a potent, highly selective small molecule inhibitor of EZH2, inhibited EZH2-mutant DLBCL more significantly in vitro and in vivo. The combination of HDAC inhibitor HBI8000 with EZH2 inhibitor SHR2554 exhibited dramatic anti-tumor activity in both mutant and wild-type DLBCL, which may become a potential therapeutic modality for the treatment of DLBCL patients. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2072-6694 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c41b0da97ba00796bca943ef5f416861 https://www.mdpi.com/2072-6694/13/17/4249 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c41b0da97ba00796bca943ef5f416861 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20726694 |
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