ArticleEMBO molecular medicine2021
Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism.
Article in EMBO molecular medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- Chronic Nitrous Oxide Exposure Disrupts Metabolism in Mice: A Plasma Untargeted Metabolomics Study.Metabolites · 2026Article
- Induction of immunogenic cell death by active components of natural products reshaping the tumor microenvironment for enhanced antitumor immunity.Frontiers in pharmacology · 2026Review
- Analysis of sex difference in strychnine-intoxicated rat based on the combination of metabolic kinetics and metabolomics.Biology of sex differences · 2025Article
- Multifaceted role of the vitamin B6 pathway in cancer: metabolism, immune interaction, and temporal and spatial regulation.Genes & development · 2025Review
- A pyrimidine metabolism-related gene signature for prognosis prediction and immune microenvironment description of breast cancer.Journal of translational medicine · 2025Article
- Review
- The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI.International journal of molecular sciences · 2023Article
- Glutamine metabolism genes prognostic signature for stomach adenocarcinoma and immune infiltration: potential biomarkers for predicting overall survival.Frontiers in oncology · 2023Article
- The integrated stress response in cancer progression: a force for plasticity and resistance.Frontiers in oncology · 2023Review
- Pyrimidine metabolism regulator-mediated molecular subtypes display tumor microenvironmental hallmarks and assist precision treatment in bladder cancer.Frontiers in oncology · 2023Article
- Article
- Review
- Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism.EMBO molecular medicine · 2021Article
- Tailored-Made Polydopamine Nanoparticles to Induce Ferroptosis in Breast Cancer Cells in Combination with Chemotherapy.International journal of molecular sciences · 2021Article
- Targeting the Integrated Stress Response in Cancer Therapy.Frontiers in pharmacology · 2021Review
Corrections and comments
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Authors and funding
25 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi-agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high-throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation-like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard-of-care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.
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