ArticleOncotarget2016
Multifactorial resistance to aminopeptidase inhibitor prodrug CHR2863 in myeloid leukemia cells: down-regulation of carboxylesterase 1, drug sequestration in lipid droplets and pro-survival activation ERK/Akt/mTOR.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- Lipid droplets as stress-buffering organelles in cancer cell homeostasis.Communications biology · 2026Review
- From Storage to Signaling: Lipid Droplet Lipolysis in Cholesterol Mobilization and Foam Cell Remodeling.Current atherosclerosis reports · 2026Review
- Lipid metabolism: a potential checkpoint for cGAS-STING regulation in colorectal cancer.Frontiers in immunology · 2026Review
- Review
- Carboxylesterase 1 regulates peroxisome proliferator-activated receptor gamma to inhibit the growth and metastasis of breast cancer cells.Journal of molecular histology · 2025Article
- Metabolism and signaling crosstalk in glioblastoma progression and therapy resistance.Molecular oncology · 2025Review
- The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression.Biomedicines · 2024Review
- An Overview on Lipid Droplets Accumulation as Novel Target for Acute Myeloid Leukemia Therapy.Biomedicines · 2023Review
- Statins markedly potentiate aminopeptidase inhibitor activity against (drug-resistant) human acute myeloid leukemia cells.Cancer drug resistance (Alhambra, Calif.) · 2023Article
- Lipid Metabolism in Glioblastoma: From De Novo Synthesis to Storage.Biomedicines · 2022Review
- The BASHY Platform Enables the Assembly of a Fluorescent Bortezomib-GV1001 Conjugate.ACS medicinal chemistry letters · 2022Article
- The CYTOLD and ERTOLD pathways for lipid droplet-protein targeting.Trends in biochemical sciences · 2022Review
- Novel Insights on Lipid Metabolism Alterations in Drug Resistance in Cancer.Frontiers in cell and developmental biology · 2022Review
- Macrophage imaging and subset analysis using single-cell RNA sequencing.Nanotheranostics · 2021Article
- Lipid droplets: platforms with multiple functions in cancer hallmarks.Cell death & disease · 2020Review
- Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention.Advanced drug delivery reviews · 2020Review
- F8-IL10: A New Potential Antirheumatic Drug Evaluated by a PET-Guided Translational Approach.Molecular pharmaceutics · 2019Article
- Imaging and Methotrexate Response Monitoring of Systemic Inflammation in Arthritic Rats Employing the Macrophage PET Tracer [Contrast media & molecular imaging · 2018Article
- Lipid droplet functions beyond energy storage.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2017Review
- Lipid Droplets: A Key Cellular Organelle Associated with Cancer Cell Survival under Normoxia and Hypoxia.International journal of molecular sciences · 2016Review
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aminopeptidase inhibitors are receiving attention as combination chemotherapeutic agents for the treatment of refractory acute myeloid leukemia. However, the factors determining therapeutic efficacy remain elusive. Here we identified the molecular basis of acquired resistance to CHR2863, an orally available hydrophobic aminopeptidase inhibitor prodrug with an esterase-sensitive motif, in myeloid leukemia cells. CHR2863 enters cells by diffusion and is retained therein upon esterase activity-mediated conversion to its hydrophilic active metabolite drug CHR6768, thereby exerting amino acid depletion. Carboxylesterases (CES) serve as candidate prodrug activating enzymes given CES1 expression in acute myeloid leukemia specimens. We established two novel myeloid leukemia sublines U937/CHR2863(200) and U937/CHR2863(5uM), with low (14-fold) and high level (270-fold) CHR2863 resistance. The latter drug resistant cells displayed: (i) complete loss of CES1-mediated drug activation associated with down-regulation of CES1 mRNA and protein, (ii) marked retention/sequestration of the prodrug, (iii) a substantial increase in intracellular lipid droplets, and (iv) a dominant activation of the pro-survival Akt/mTOR pathway. Remarkably, the latter feature coincided with a gain of sensitivity to the mTOR inhibitor rapamycin. These finding delineate the molecular basis of CHR2863 resistance and offer a novel modality to overcome this drug resistance in myeloid leukemia cells.
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