دورية أكاديمية
أعرض في EDS

Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma.

التفاصيل البيبلوغرافية
العنوان: Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma.
المؤلفون: Xie Y; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Wang Y; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Xu Z; 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., Lu Y; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Song D; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Gao L; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Yu D; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Li B; 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., Chen G; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Zhang H; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Feng Q; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Zhang Y; 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., Hu K; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Huang C; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Peng Y; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Wu X; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China., Mao Z; 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 University, Shanghai, 200092, China., Shao J; 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. shaojimin@zju.edu.cn., Zhu W; 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. wlzhu@simm.ac.cn., Shi J; Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China. shijumei@tongji.edu.cn.
المصدر: Journal of biomedical science [J Biomed Sci] 2022 May 12; Vol. 29 (1), pp. 32. Date of Electronic Publication: 2022 May 12.
نوع المنشور: Clinical Trial, Phase I; Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 9421567 Publication Model: Electronic Cited Medium: Internet ISSN: 1423-0127 (Electronic) Linking ISSN: 10217770 NLM ISO Abbreviation: J Biomed Sci Subsets: MEDLINE
أسماء مطبوعة: Publication: 2009- : London : BioMed Central
Original Publication: Basel ; New York : S. Karger Medical and Scientific Publishers, c1994-
مواضيع طبية MeSH: Multiple Myeloma*/drug therapy , Multiple Myeloma*/genetics , Ribonucleotide Reductases*/genetics , Ribonucleotide Reductases*/metabolism, DNA Breaks, Double-Stranded ; DNA Damage ; DNA Repair ; DNA Replication ; Humans
مستخلص: 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.
Trial Registration: ClinicalTrials.gov, NCT03670173, Registered 12 September 2018.
(© 2022. The Author(s).)
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معلومات مُعتمدة: 82170200 National Natural Science Foundation of China; 82170201 National Natural Science Foundation of China; 81870158 National Natural Science Foundation of China; 81900212 National Natural Science Foundation of China; 2016YFA0502301 National Key Research and Development Program of China
فهرسة مساهمة: Keywords: 4-Hydroxysalicylanilid; DNA damage repair; Deoxyribonucleotides; Multiple myeloma; Ribonucleotide reductase
سلسلة جزيئية: ClinicalTrials.gov NCT03670173
المشرفين على المادة: EC 1.17.4.- (Ribonucleotide Reductases)
تواريخ الأحداث: Date Created: 20220513 Date Completed: 20220517 Latest Revision: 20220716
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC9097096
DOI: 10.1186/s12929-022-00813-2
PMID: 35546402
قاعدة البيانات: MEDLINE
الوصف
تدمد:1423-0127
DOI:10.1186/s12929-022-00813-2