ArticleLeukemia2016
A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells.
Article in Leukemia, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
49 citing papers in PubMed, 84 citations in OpenAlex.
- Results from a biomarker study to accompany a phase II trial of RRx-001 with reintroduced platinum-based chemotherapy in relapsed small cell carcinoma.Expert opinion on investigational drugs · 2021Trial
- Epigenetic modifications of the PHOX2A and CDH2 genes expression- new insights into the pathogenesis of multiple myeloma.BMC cancer · 2025Article
- Acquired Bortezomib Resistance in Multiple Myeloma: From Mechanisms to Strategy.Current treatment options in oncology · 2024Review
- Mitochondrial Dysfunction in Parkinson's Disease: A Contribution to Cognitive Impairment?International journal of molecular sciences · 2024Review
- Impact of Growth Conditions on High-Throughput Identification of Repurposing Drugs forAntibiotics (Basel, Switzerland) · 2024Article
- Drug resistance mechanisms and treatment strategies mediated by Ubiquitin-Specific Proteases (USPs) in cancers: new directions and therapeutic options.Molecular cancer · 2024Review
- Anti-tumor and anti-metastatic effects of RRx-001 on hepatocellular carcinoma: mechanisms of action and therapeutic potential.Frontiers in pharmacology · 2024Article
- Review
- Targeting ubiquitin specific proteases (USPs) in cancer immunotherapy: from basic research to preclinical application.Journal of experimental & clinical cancer research : CR · 2023Review
- A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation.Drugs · 2023Review
- Review
- A multicenter, phase 1, dose escalation clinical trial (G-FORCE-1) of XRT, RRx-001 and temozolomide followed by temozolomide +/- RRx-001 in newly diagnosed glioblastoma.Frontiers in oncology · 2023Article
- RRx-001: a chimeric triple action NLRP3 inhibitor, Nrf2 inducer, and nitric oxide superagonist.Frontiers in oncology · 2023Review
- DNA methyltransferase-1 in acute myeloid leukaemia: beyond the maintenance of DNA methylation.Annals of medicine · 2022Review
- Review
- Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils.Cancers · 2022Review
- Crosstalk of Epigenetic and Metabolic Signaling Underpinning Glioblastoma Pathogenesis.Cancers · 2022Review
- Epigenetic Crosstalk between Malignant Plasma Cells and the Tumour Microenvironment in Multiple Myeloma.Cancers · 2022Review
- Interference With Redox Homeostasis Through a G6PD-Targeting Self-Assembled Hydrogel for the Enhancement of Sonodynamic Therapy in Breast Cancer.Frontiers in chemistry · 2022Article
- Shikonin impedes type 2 ovarian cancer progression via FasL/caspase-8 and mir-874-3p/XIAP axis and prohibits the properties of stemness.American journal of cancer research · 2022Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
The hypoxic bone marrow (BM) microenvironment confers growth/survival and drug resistance in multiple myeloma (MM) cells. Novel therapies targeting the MM cell in its hypoxic BM milieu may overcome drug resistance. Recent studies led to the development of a novel molecule RRx-001 with hypoxia-selective epigenetic and nitric oxide-donating properties. Here, we demonstrate that RRx-001 decreases the viability of MM cell lines and primary patient cells, as well as overcomes drug resistance. RRx-001 inhibits MM cell growth in the presence of BM stromal cells. RRx-001-induced apoptosis is associated with: (i) activation of caspases; (ii) release of ROS and nitrogen species; (iii) induction of DNA damage via ATM/γ-H2AX; and (iv) decrease in DNA methyltransferase (DNMT) and global methylation. RNA interference study shows a predominant role of DNMT1 in MM cell survival versus DNMT3a or DNMT3b. The deubiquitylating enzyme USP7 stimulates DNMT1 activity, and conversely, USP7-siRNA reduced DNMT1 activity and decreased MM cell viability. RRx-001 plus USP7 inhibitor P5091 triggered synergistic anti-MM activity. MM xenograft studies show that RRx-001 is well tolerated, inhibits tumor growth and enhances survival. Combining RRx-001 with pomalidomide, bortezomib or SAHA induces synergistic anti-MM activity. Our results provide the rationale for translation of RRx-001, either alone or in combination, to clinical evaluation in MM.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.