ArticleProceedings of the National Academy of Sciences of the United States of America2010
Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers, 1 of them a synthesis that pooled it.
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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
68 citing papers in PubMed, 1 synthesis or guideline pooled it, 124 citations in OpenAlex.
- Drug repurposing on Alzheimer's disease through modulation of NRF2 neighborhood.Redox biology · 2023Pooled it
- Microparticles synthesized from itaconate polyesters enable metabolite delivery and elicit immunoregulatory outcomes.Journal of controlled release : official journal of the Controlled Release Society · 2026Article
- Review
- Crosstalk Between Autophagy and Oxidative Stress in Hematological Malignancies: Mechanisms, Implications, and Therapeutic Potential.Antioxidants (Basel, Switzerland) · 2025Review
- Parthenolide: pioneering new frontiers in hematological malignancies.Frontiers in pharmacology · 2025Review
- Facts, Dogmas, and Unknowns About Mitochondrial Reactive Oxygen Species in Cancer.Antioxidants (Basel, Switzerland) · 2024Review
- Synthesis and Biochemical Evaluation of Ethanoanthracenes and Related Compounds: Antiproliferative and Pro-Apoptotic Effects in Chronic Lymphocytic Leukemia (CLL).Pharmaceuticals (Basel, Switzerland) · 2024Article
- Nrf2-Regulated Antioxidant System in Cells of In Vivo Drug-Resistant P388 Murine Leukemia Strains.Bulletin of experimental biology and medicine · 2024Article
- Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death.Cell death & disease · 2024Article
- Immune checkpoints represent a promising breakthrough in targeted therapy and prognosis of myelodysplastic syndrome.Heliyon · 2023Review
- Ferroptosis-modulating small molecules for targeting drug-resistant cancer: Challenges and opportunities in manipulating redox signaling.Medicinal research reviews · 2023Review
- Study of Cannabis Oils Obtained from Three Varieties ofPlants (Basel, Switzerland) · 2023Article
- Ethacrynic Acid: A Promising Candidate for Drug Repurposing as an Anticancer Agent.International journal of molecular sciences · 2023Review
- Reversibility and Low Commitment to Forward Catalysis in the Conjugation of Lipid Alkenals by Glutathione Transferase A4-4.Biomolecules · 2023Article
- Protein Phosphorylation and Redox Status: An as Yet Elusive Dyad in Chronic Lymphocytic Leukemia.Cancers · 2022Review
- Article
- An Overview of NRF2-Activating Compounds Bearing α,β-Unsaturated Moiety and Their Antioxidant Effects.International journal of molecular sciences · 2022Review
- Cell-Based Assays to Identify Modulators of Nrf2/ARE Pathway.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells.Biomedicines · 2021Article
- Article
8 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Recent studies show that redox-active small molecules are selectively cytotoxic to chronic lymphocytic leukemia (CLL). Although elevated levels of reactive oxygen species in CLL cells have been implicated, the molecular mechanism underlying this selectivity is unclear. In other cell types, the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway regulates the oxidative stress response. We found elevated Nrf2 signaling in untreated CLL cells compared with normal lymphocytes. Therefore, we tested 27 known electrophilic and antioxidant compounds with drug-like properties and determined their CLL-selective cytotoxicity and effect on Nrf2 signaling. The selected compounds were from five distinct structural classes; alpha-beta unsaturated carbonyls, isothiocyanates, sulfhydryl reactive metals, flavones, and polyphenols. Our results show that compounds containing alpha-beta unsaturated carbonyls, sulfhydryl reactive metals, and isothiocyanates are strong activators of Nrf2 in a reporter assay system and in primary human CLL based on increased expression of the Nrf2 target heme oxygenase-1. alpha-beta Unsaturated carbonyl-containing compounds were selectively cytotoxic to CLL, and loss of the alpha-beta unsaturation abrogated Nrf2 activity and CLL toxicity. The alpha-beta unsaturated carbonyl containing compounds ethacrynic acid and parthenolide activated Nrf2 in normal peripheral blood mononuclear cells, but had a less potent effect in CLL cells. Furthermore, ethacrynic acid bound directly to the Nrf2-negative regulator Kelch-like ECH-associated protein 1 (Keap1) in CLL cells. These experiments document the presence of Nrf2 signaling in human CLL and suggest that altered Nrf2 responses may contribute to the observed selective cytotoxicity of electrophilic compounds in this disease.
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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.