- 作者: Yongsheng Xie, Yingcong Wang, Zhijian Xu, Yumeng Lu, Dongliang Song, Lu Gao, Dandan Yu, Bo Li, Gege Chen, Hui Zhang, Qilin Feng, Yong Zhang, Ke Hu, Cheng Huang, Yu Peng, Xiaosong Wu, Zhiyong Mao, Jimin Shao, Weiliang Zhu & Jumei Shi
- 作者服務機構: 1.CAS Key Laboratory of Receptor Research; State Key Laboratory of Drug Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China 2.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, Tongji 3.Department of Hematology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China 4.Department of Pathology and Pathophysiology, Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University Cancer Center, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang, China 5.Yongsheng Xie, Yingcong Wang and Zhijian Xu contributed equally to this work
- 中文摘要:
- 英文摘要:
Background
Aberrant 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.
Methods
We 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.
Results
HDS 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.
Conclusions
Our 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. - 中文關鍵字:
- 英文關鍵字: 4-Hydroxysalicylanilid, Ribonucleotide reductase, Deoxyribonucleotides, DNA damage repair, Multiple myeloma