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Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma
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 bio...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097096/ https://www.ncbi.nlm.nih.gov/pubmed/35546402 http://dx.doi.org/10.1186/s12929-022-00813-2 |
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author | Xie, Yongsheng Wang, Yingcong Xu, Zhijian Lu, Yumeng Song, Dongliang Gao, Lu Yu, Dandan Li, Bo Chen, Gege Zhang, Hui Feng, Qilin Zhang, Yong Hu, Ke Huang, Cheng Peng, Yu Wu, Xiaosong Mao, Zhiyong Shao, Jimin Zhu, Weiliang Shi, Jumei |
author_facet | Xie, Yongsheng Wang, Yingcong Xu, Zhijian Lu, Yumeng Song, Dongliang Gao, Lu Yu, Dandan Li, Bo Chen, Gege Zhang, Hui Feng, Qilin Zhang, Yong Hu, Ke Huang, Cheng Peng, Yu Wu, Xiaosong Mao, Zhiyong Shao, Jimin Zhu, Weiliang Shi, Jumei |
author_sort | Xie, Yongsheng |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12929-022-00813-2. |
format | Online Article Text |
id | pubmed-9097096 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-90970962022-05-13 Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma Xie, Yongsheng Wang, Yingcong Xu, Zhijian Lu, Yumeng Song, Dongliang Gao, Lu Yu, Dandan Li, Bo Chen, Gege Zhang, Hui Feng, Qilin Zhang, Yong Hu, Ke Huang, Cheng Peng, Yu Wu, Xiaosong Mao, Zhiyong Shao, Jimin Zhu, Weiliang Shi, Jumei J Biomed Sci Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12929-022-00813-2. BioMed Central 2022-05-12 /pmc/articles/PMC9097096/ /pubmed/35546402 http://dx.doi.org/10.1186/s12929-022-00813-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Xie, Yongsheng Wang, Yingcong Xu, Zhijian Lu, Yumeng Song, Dongliang Gao, Lu Yu, Dandan Li, Bo Chen, Gege Zhang, Hui Feng, Qilin Zhang, Yong Hu, Ke Huang, Cheng Peng, Yu Wu, Xiaosong Mao, Zhiyong Shao, Jimin Zhu, Weiliang Shi, Jumei Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma |
title | Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma |
title_full | Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma |
title_fullStr | Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma |
title_full_unstemmed | Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma |
title_short | Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma |
title_sort | preclinical validation and phase i trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dntp synthesis in multiple myeloma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097096/ https://www.ncbi.nlm.nih.gov/pubmed/35546402 http://dx.doi.org/10.1186/s12929-022-00813-2 |
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