ArticleOncotarget2018
Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells.
Article in Oncotarget, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 63 citations in OpenAlex.
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- Mitochondria-targeted metformin analogs activate the ER stress-unfolded protein response pathway to drive apoptosis in pancreatic cancer.Cell death & disease · 2026Article
- The Role of Mitochondrial ROS in Neoplastic Transformations, Progression and Therapeutic Targeting.Oncology research · 2026Review
- Dysregulation of Mitochondrial Function in Cancer Cells.International journal of molecular sciences · 2025Review
- Complementary approaches define the metabolic features that accompany Richter syndrome transformation.Cellular and molecular life sciences : CMLS · 2025Article
- AMP-activated protein kinase mediates adaptation of glioblastoma cells to conditions of the tumor microenvironment.Journal of experimental & clinical cancer research : CR · 2025Article
- Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival.Cell communication and signaling : CCS · 2025Article
- Leader Cells: Invade and Evade-The Frontline of Cancer Progression.International journal of molecular sciences · 2024Review
- Therapeutic modulation of ROCK overcomes metabolic adaptation of cancer cells to OXPHOS inhibition and drives synergistic anti-tumor activity.bioRxiv : the preprint server for biology · 2024Article
- Mitochondrial Elongation and ROS-Mediated Apoptosis in Prostate Cancer Cells under Therapy with Apalutamide and Complex I Inhibitor.International journal of molecular sciences · 2024Article
- Chronic lymphocytic leukemia patient-derived xenografts recapitulate clonal evolution to Richter transformation.Leukemia · 2024Article
- Electron transport chain and mTOR inhibition synergistically decrease CD40 signaling and counteract venetoclax resistance in chronic lymphocytic leukemia.Haematologica · 2024Article
- Pan-tissue mitochondrial phenotyping reveals lower OXPHOS expression and function across cancer types.Scientific reports · 2023Article
- Article
- Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC-driven lymphoma.EMBO molecular medicine · 2023Article
- Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.Nature communications · 2023Article
- Subtype and Site Specific-Induced Metabolic Vulnerabilities in Prostate Cancer.Molecular cancer research : MCR · 2023Article
- Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia.Frontiers in oncology · 2023Article
- Genetics of enzymatic dysfunctions in metabolic disorders and cancer.Frontiers in oncology · 2023Review
- Mesenchymal stromal cells, metabolism, and mitochondrial transfer in bone marrow normal and malignant hematopoiesis.Frontiers in cell and developmental biology · 2023Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Blood cells from patients with chronic lymphocytic leukemia (CLL) are replicationally quiescent but transcriptionally, translationally, and metabolically active. Recently, we demonstrated that oxidative phosphorylation (OxPhos) is a predominant pathway in CLL for energy production and is further augmented in the presence of the stromal microenvironment. Importantly, CLL cells from patients with poor prognostic markers showed increased OxPhos. From these data, we theorized that OxPhos can be targeted to treat CLL. IACS-010759, currently in clinical development, is a small-molecule, orally bioavailable OxPhos inhibitor that targets mitochondrial complex I. Treatment of primary CLL cells with IACS-010759 greatly inhibited OxPhos but caused only minor cell death at 24 and 48 h. In the presence of stroma, the drug successfully inhibited OxPhos and diminished intracellular ribonucleotide pools. However, glycolysis and glucose uptake were induced as compensatory mechanisms. To mitigate the upregulated glycolytic flux, we used 2-deoxy-D-glucose in combination with IACS-010759. This combination reduced both OxPhos and glycolysis and induced cell death. Consistent with these data, low-glucose culture conditions sensitized CLL cells to IACS-010759. Collectively, these data suggest that CLL cells adapt to use a different metabolic pathway when OxPhos is inhibited and that targeting both OxPhos and glycolysis pathways is necessary for biological effect.
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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.