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

Abstract

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.

Non-Cicatricial Alopecia and Its Association with Anthropometric Measurements and Nutritional Laboratory Markers

“…Although the exact mechanism of how a low ferritin concentration leads to hair loss has not been fully elucidated, one theory emphasizes the role of iron as a cofactor for ribonucleotide reductase. This iron-dependent enzyme is also the rate-limiting enzyme for the biosynthesis of deoxyribonucleotides (dNTPs), which are essential for DNA replication and DNA damage repair [36]. Since hair follicle cells divide rapidly, they require constant use of ribonucleotide reductase.…”

Yeast Ribonucleotide Reductase Is a Direct Target of the Proteasome and Provides Hyper Resistance to the Carcinogen 4-NQO

“…Taken together, these data suggest that the combination of proteasome and RNR inhibitors may be more effective in treating cancer. Indeed, the synergistic anti-tumor effect of the combination of 4-hydroxysalicylanilide (targeting RRM2) together with the proteasome inhibitor Bortezomib has been shown in multiple myeloma cell lines, including primary CD138+ cells from Bortezomib-refractory patients [ 71 ].…”

Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma

“…Cell lines were purchased from the American Type Culture Collection (Mananssas, VA, USA) or obtained as described in our previous articles. 25 , 26 All samples were obtained from patients with MM and normal donors who gave informed consent in accordance with the Declaration of Helsinki. Approval was obtained by the Shanghai Tenth People’s Hospital Institutional Review Board.…”