ArticleCell death & disease2017
Functional inhibition of acid sphingomyelinase by Fluphenazine triggers hypoxia-specific tumor cell death.
Article in Cell death & disease, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 41 citations in OpenAlex.
- Repurposing Antipsychotics in Cancer Therapy: Modulation of Autophagy Mechanisms.Clinical drug investigation · 2026Review
- Anticancer Effects of Fluphenazine Alone and in Combination with Cisplatin in Gastric Cancer Cells and a Mouse Xenograft Model.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Cohort-Scale Spatial Autocorrelation for Tumor Prediction in Mid-Infrared Pathology and Spatial Biomarker Discovery Using MALDI Imaging Lipidomics.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Phenothiazine Derivatives and Their Impact on the Apoptosis Processes: A Review.Journal of applied toxicology : JAT · 2026Review
- A Review Discussing Synthesis and Translational Studies of Medicinal Agents Targeting Sphingolipid Pathways.Biomolecules · 2025Review
- Lipids: Driving Forces in the Underlying Biology of Carcinogenesis.ACS pharmacology & translational science · 2025Review
- Cell Painting PLUS: expanding the multiplexing capacity of Cell Painting-based phenotypic profiling using iterative staining-elution cycles.Nature communications · 2025Article
- Molecular docking as a tool for the discovery of novel insight about the role of acid sphingomyelinase inhibitors in SARS- CoV-2 infectivity.BMC public health · 2024Review
- Article
- The Applications and Challenges of the Development ofCellular and molecular bioengineering · 2023Review
- Peripheralized sepiapterin reductase inhibition as a safe analgesic therapy.Frontiers in pharmacology · 2023Review
- Repurposing phenothiazines for cancer therapy: compromising membrane integrity in cancer cells.Frontiers in oncology · 2023Review
- Antipsychotic Drug Fluphenazine against Human Cancer Cells.Biomolecules · 2022Review
- Harnessing the power of sphingolipids: Prospects for acute myeloid leukemia.Blood reviews · 2022Review
- Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer.Pharmaceutics · 2022Article
- Lipidomic profiling reveals lipid regulation by a novel LSD1 inhibitor treatment.Oncology reports · 2021Article
- Article
- Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro.Journal of lipid research · 2020Article
- Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention.Advanced drug delivery reviews · 2020Review
- Antineoplastic Agents Targeting Sphingolipid Pathways.Frontiers in oncology · 2020Review
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Owing to lagging or insufficient neo-angiogenesis, hypoxia is a feature of most solid tumors. Hypoxic tumor regions contribute to resistance against antiproliferative chemotherapeutics, radiotherapy and immunotherapy. Targeting cells in hypoxic tumor areas is therefore an important strategy for cancer treatment. Most approaches for targeting hypoxic cells focus on the inhibition of hypoxia adaption pathways but only a limited number of compounds with the potential to specifically target hypoxic tumor regions have been identified. By using tumor spheroids in hypoxic conditions as screening system, we identified a set of compounds, including the phenothiazine antipsychotic Fluphenazine, as hits with novel mode of action. Fluphenazine functionally inhibits acid sphingomyelinase and causes cellular sphingomyelin accumulation, which induces cancer cell death specifically in hypoxic tumor spheroids. Moreover, we found that functional inhibition of acid sphingomyelinase leads to overactivation of hypoxia stress-response pathways and that hypoxia-specific cell death is mediated by the stress-responsive transcription factor ATF4. Taken together, the here presented data suggest a novel, yet unexplored mechanism in which induction of sphingolipid stress leads to the overactivation of hypoxia stress-response pathways and thereby promotes their pro-apoptotic tumor-suppressor functions to specifically kill cells in hypoxic tumor areas.
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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.