ArticleThe Journal of biological chemistry2012
Structure-activity analysis of niclosamide reveals potential role for cytoplasmic pH in control of mammalian target of rapamycin complex 1 (mTORC1) signaling.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 104 papers.
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Who cites it
104 citing papers in PubMed, 160 citations in OpenAlex.
- Trial
- Review on drug repositioning of some FDA-approved drugs for treatment of cancer/microbial diseases.RSC advances · 2026Review
- Repurposing niclosamide to mitigate inflammaging: a review of multi-target mechanisms in cellular senescence and age-related decline.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Niclosamide extends health span and reduces frailty by ameliorating mTORC1 hyperactivation in aging models.Journal of advanced research · 2026Article
- Integrative Network-Based Transcriptomic Analysis Identifies Niclosamide as a Candidate Repositioned Drug for Breast Cancer.Breast cancer (Dove Medical Press) · 2026Article
- In Vitro Inhibition ofPathogens (Basel, Switzerland) · 2025Article
- Valine-Niclosamide for Treatment of Androgen Receptor Splice Variant-Positive Hepatocellular Carcinoma.Cancers · 2025Article
- Niclosamide-Loaded Polyanhydride Nanoparticles to Combat Gemcitabine Resistance in Pancreatic Cancer.Regenerative engineering and translational medicine · 2025Article
- Exploring the impact of mitochondrial-targeting anthelmintic agents with GLUT1 inhibitor BAY-876 on breast cancer cell metabolism.BMC cancer · 2024Article
- Optimizing Niclosamide for Cancer Therapy: Improving Bioavailability via Structural Modification and Nanotechnology.Cancers · 2024Review
- Pharmacological investigation of new niclosamide-based isatin hybrids as antiproliferative, antioxidant, and apoptosis inducers.Scientific reports · 2024Article
- Use of Viscous medium to study anthelmintic drug action in Caenorhabditis elegans.Scientific reports · 2024Article
- Review
- Niclosamide, but not ivermectin, inhibits anoctamin 1 and 6 and attenuates inflammation of the respiratory tract.Pflugers Archiv : European journal of physiology · 2024Article
- TP53 Alterations in Myelodysplastic Syndromes and Acute Myeloid Leukemia.Biomedicines · 2023Review
- Wnt Signaling Inhibitors and Their Promising Role in Tumor Treatment.International journal of molecular sciences · 2023Review
- Phenolic Acids-Mediated Regulation of Molecular Targets in Ovarian Cancer: Current Understanding and Future Perspectives.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Article
- Androgen receptor-dependent regulation of metabolism in high grade bladder cancer cells.Scientific reports · 2023Article
- Article
44 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
Abstract
Mammalian target of rapamycin complex 1 (mTORC1) signaling is frequently dysregulated in cancer. Inhibition of mTORC1 is thus regarded as a promising strategy in the treatment of tumors with elevated mTORC1 activity. We have recently identified niclosamide (a Food and Drug Administration-approved antihelminthic drug) as an inhibitor of mTORC1 signaling. In the present study, we explored possible mechanisms by which niclosamide may inhibit mTORC1 signaling. We tested whether niclosamide interferes with signaling cascades upstream of mTORC1, the catalytic activity of mTOR, or mTORC1 assembly. We found that niclosamide does not impair PI3K/Akt signaling, nor does it inhibit mTORC1 kinase activity. We also found that niclosamide does not interfere with mTORC1 assembly. Previous studies in helminths suggest that niclosamide disrupts pH homeostasis of the parasite. This prompted us to investigate whether niclosamide affects the pH balance of cancer cells. Experiments in both breast cancer cells and cell-free systems demonstrated that niclosamide possesses protonophoric activity in cells and in vitro. In cells, niclosamide dissipated protons (down their concentration gradient) from lysosomes to the cytosol, effectively lowering cytoplasmic pH. Notably, analysis of five niclosamide analogs revealed that the structural features of niclosamide required for protonophoric activity are also essential for mTORC1 inhibition. Furthermore, lowering cytoplasmic pH by means other than niclosamide treatment (e.g. incubation with propionic acid or bicarbonate withdrawal) recapitulated the inhibitory effects of niclosamide on mTORC1 signaling, lending support to a possible role for cytoplasmic pH in the control of mTORC1. Our data illustrate a potential mechanism for chemical inhibition of mTORC1 signaling involving modulation of cytoplasmic pH.
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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.