Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma
文献类型：期刊论文
| 作者 | Xie,Yongsheng2; Wang,Yingcong2; Xu,Zhijian3 ; Lu,Yumeng2; Song,Dongliang2; Gao,Lu2; Yu,Dandan2; Li,Bo3; Chen,Gege2; Zhang,Hui2
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| 刊名 | Journal of Biomedical Science
 |
| 出版日期 | 2022-05-12 |
| 卷号 | 29期号:1 |
| 关键词 | 4-Hydroxysalicylanilid Ribonucleotide reductase Deoxyribonucleotides DNA damage repair Multiple myeloma |
| DOI | 10.1186/s12929-022-00813-2 |
| 通讯作者 | Shao,Jimin(shaojimin@zju.edu.cn) ; Zhu,Weiliang(wlzhu@simm.ac.cn) ; Shi,Jumei(shijumei@tongji.edu.cn) |
| 英文摘要 | AbstractBackgroundAberrant DNA repair pathways contribute to malignant transformation or disease progression and the acquisition of drug resistance in multiple myeloma (MM); therefore, these pathways could be therapeutically exploited. Ribonucleotide reductase (RNR) is the rate-limiting enzyme for the biosynthesis of deoxyribonucleotides (dNTPs), which are essential for DNA replication and DNA damage repair. In this study, we explored the efficacy of the novel RNR inhibitor, 4-hydroxysalicylanilide (HDS), in myeloma cells and xenograft model. In addition, we assessed the clinical activity and safety of HDS in patients with MM.MethodsWe applied bioinformatic, genetic, and pharmacological approaches to demonstrate that HDS was an RNR inhibitor that directly bound to RNR subunit M2 (RRM2). The activity of HDS alone or in synergy with standard treatments was evaluated in vitro and in vivo. We also initiated a phase I clinical trial of single-agent HDS in MM patients (ClinicalTrials.gov: NCT03670173) to assess safety and efficacy.ResultsHDS inhibited the activity of RNR by directly targeting RRM2. HDS decreased the RNR-mediated dNTP synthesis and concomitantly inhibited DNA damage repair, resulting in the accumulation of endogenous unrepaired DNA double-strand breaks (DSBs), thus inhibiting MM cell proliferation and inducing apoptosis. Moreover, HDS overcame the protective effects of IL-6, IGF-1 and bone marrow stromal cells (BMSCs) on MM cells. HDS prolonged survival in a MM xenograft model and induced synergistic anti-myeloma activity in combination with melphalan and bortezomib. HDS also showed a favorable safety profile and demonstrated clinical activity against MM.ConclusionsOur study provides a rationale for the clinical evaluation of HDS as an anti-myeloma agent, either alone or in combination with standard treatments for MM.Trial registration: ClinicalTrials.gov, NCT03670173, Registered 12 September 2018. |
| 语种 | 英语 |
| 出版者 | BioMed Central |
| WOS记录号 | BMC:10.1186/S12929-022-00813-2 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/299555]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Shao,Jimin; Zhu,Weiliang; Shi,Jumei; Zhu, Weiliang |
| 作者单位 | 1.Zhejiang University School of Medicine, Zhejiang University Cancer Center; Department of Pathology and Pathophysiology, Cancer Institute of the Second Affiliated Hospital 2.Shanghai Tenth People’s Hospital, Tongji University School of Medicine; Department of Hematology 3.Chinese Academy of Sciences; CAS Key Laboratory of Receptor Research; State Key Laboratory of Drug Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica 4.Tongji University; Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology |
| 推荐引用方式 GB/T 7714 | Xie,Yongsheng,Wang,Yingcong,Xu,Zhijian,et al. Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma[J]. Journal of Biomedical Science,2022,29(1). |
| APA | Xie,Yongsheng.,Wang,Yingcong.,Xu,Zhijian.,Lu,Yumeng.,Song,Dongliang.,...&Xu, Zhijian.(2022).Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma.Journal of Biomedical Science,29(1). |
| MLA | Xie,Yongsheng,et al."Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma".Journal of Biomedical Science 29.1(2022). |
入库方式： OAI收割
来源：上海药物研究所
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