ArticleCancer research2024
Simultaneous Targeting of NQO1 and SOD1 Eradicates Breast Cancer Stem Cells via Mitochondrial Futile Redox Cycling.
Article in Cancer research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- 7-Deshydroxypyrogallin-4-carboxylic acid dietary phytochemical as a putative FTO inhibitor in breast cancer: an integrated computational and cytotoxicity study.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Tumor heterogeneity: development, mechanisms, and therapeutic implications.Signal transduction and targeted therapy · 2026Review
- A Noncanonical RNA-Binding Function of NQO1 Drives Angiogenesis in Esophageal Squamous Cell Carcinoma via Extracellular Vesicle-Mediated AGRN Transfer.Cancer research · 2026Article
- Ligand-dependent corepressor suppresses angiogenesis and macrophage infiltration in gliobl astoma microenvironment via MCP-1 down-regulation.BMC biotechnology · 2026Article
- Reactive oxygen species (ROS) in cancer: from mechanism to therapeutic implications.Signal transduction and targeted therapy · 2026Review
- A computational framework integrating multi-omics and machine learning for identifying glycolytic gene markers in breast cancer.Discover oncology · 2026Article
- Low-dose X-ray-activated radiodynamic therapy via a lutetium-coordinated nanoplatform synergizing PARP inhibition and ferroptosis.Journal of nanobiotechnology · 2026Article
- Mitochondrial Redox Vulnerabilities in Triple-Negative Breast Cancer: Integrative Perspectives and Emerging Therapeutic Strategies.Metabolites · 2026Review
- The multifaceted roles of mitochondria and their therapeutic transformation: a new perspective on triple-negative breast cancer treatment.Frontiers in oncology · 2026Article
- Occupational and environmental iron exposure: a hidden risk factor in breast cancer etiology.Annals of medicine and surgery (2012) · 2026Review
- The role and application potential of cytochrome c in breast cancer therapy.Discover oncology · 2025Review
- Targeting the redox-programmed cell death axis in breast cancer: from molecular mechanisms to therapeutic resistance.Cell death discovery · 2025Review
- NRF2 promotes the migration of ovarian cancer cell lines by targeting TAGLN mediated epithelial-mesenchymal transition.Journal of ovarian research · 2025Article
- Unraveling systemic responses to NQO1-activated IB-DNQ and Rucaparib single and dual agent therapy in triple-negative breast cancers.bioRxiv : the preprint server for biology · 2025Article
- Role of Oxidative Stress in the Occurrence, Development, and Treatment of Breast Cancer.Antioxidants (Basel, Switzerland) · 2025Review
- Nuclear factor erythroid 2-related factor 2 as targets to treat chronic obstructive pulmonary disease: toward new perspectives.Therapeutic advances in respiratory diseaseReview
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Authors and funding
15 authors.
Funding
Abstract
Triple-negative breast cancer (TNBC) contains the highest proportion of cancer stem-like cells (CSC), which display intrinsic resistance to currently available cancer therapies. This therapeutic resistance is partially mediated by an antioxidant defense coordinated by the transcription factor NRF2 and its downstream targets that include NAD(P)H quinone oxidoreductase 1 (NQO1). In this study, we identified the antioxidant enzymes NQO1 and superoxide dismutase 1 (SOD1) as therapeutic vulnerabilities of ALDH+ epithelial-like CSCs and CD24-/loCD44+/hi mesenchymal-like CSCs in TNBC. Effective targeting of these CSC states was achieved by using isobutyl-deoxynyboquinone (IB-DNQ), a potent and specific NQO1-bioactivatable futile redox cycling molecule, which generated large amounts of reactive oxygen species including superoxide and hydrogen peroxide. Furthermore, the CSC killing effect was specifically enhanced by genetic or pharmacologic inhibition of SOD1, a copper-containing superoxide dismutase highly expressed in TNBC. Mechanistically, a significant portion of NQO1 resides in the mitochondrial intermembrane space, catalyzing futile redox cycling from IB-DNQ to generate high levels of mitochondrial superoxide, and SOD1 inhibition markedly potentiated this effect, resulting in mitochondrial oxidative injury, cytochrome c release, and activation of the caspase-3-mediated apoptotic pathway. Treatment with IB-DNQ alone or together with SOD1 inhibition effectively suppressed tumor growth, metastasis, and tumor-initiating potential in xenograft models of TNBC expressing different levels of NQO1. This futile oxidant-generating strategy, which targets CSCs across the epithelial-mesenchymal continuum, could be a promising therapeutic approach for treating patients with TNBC. Significance: Combining NQO1-bioactivatable futile oxidant generators with SOD1 inhibition eliminates breast cancer stem cells, providing a therapeutic strategy that may have wide applicability, as NQO1 and SOD1 are overexpressed in several cancers.
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