ArticleACS chemical biology2017
Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis.
Article in ACS chemical biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 86 citations in OpenAlex.
- Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights.RSC advances · 2026Review
- METTL7A inhibits progression of colorectal cancer through the SREBP1 / FDFT1 / SQLE / CYP51A1 / cholesterol metabolic pathway.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- A Phase I Study of Hydroxychloroquine and Suba-Itraconazole in Men with Biochemical Relapse of Prostate Cancer (HITMAN-PC): Dose Escalation Results.Cancer research communications · 2026Article
- Research progress on cholesterol metabolism and tumor therapy.Discover oncology · 2025Review
- Upregulation of NPC1 and its association with poor prognosis in gastric cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2024Article
- Why make it if you can take it: review on extracellular cholesterol uptake and its importance in breast and ovarian cancers.Journal of experimental & clinical cancer research : CR · 2024Review
- Article
- Potential Use of the Cholesterol Transfer Inhibitor U18666A as a Potent Research Tool for the Study of Cholesterol Mechanisms in Neurodegenerative Disorders.Molecular neurobiology · 2024Review
- Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities.International journal of biological sciences · 2024Review
- Multiplex immunohistochemistry defines two cholesterol metabolism patterns predicting immunotherapeutic outcomes in gastric cancer.Journal of translational medicine · 2023Article
- Repurposing antifungal drugs for cancer therapy.Journal of advanced research · 2023Review
- Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic Steatohepatitis.International journal of molecular sciences · 2022Article
- High-affinity SOAT1 ligands remodeled cholesterol metabolism program to inhibit tumor growth.BMC medicine · 2022Article
- Article
- Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management.Journal of hematology & oncology · 2022Review
- Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance.International journal of molecular sciences · 2022Review
- Repurposing Itraconazole and Hydroxychloroquine to Target Lysosomal Homeostasis in Epithelial Ovarian Cancer.Cancer research communications · 2022Article
- Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing.Medical sciences (Basel, Switzerland) · 2022Review
- Repurposing Antifungals for Host-Directed Antiviral Therapy?Pharmaceuticals (Basel, Switzerland) · 2022Review
- Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein.Autophagy · 2021Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
The antifungal drug itraconazole was recently found to exhibit potent antiangiogenic activity and has since been repurposed as an investigational anticancer agent. Itraconazole has been shown to exert its antiangiogenic activity through inhibition of the mTOR signaling pathway, but the molecular mechanism of action was unknown. We recently identified the mitochondrial protein VDAC1 as a target of itraconazole and a mediator of its activation of AMPK, an upstream regulator of mTOR. However, VDAC1 could not account for the previously reported inhibition of cholesterol trafficking by itraconazole, which was also demonstrated to lead to mTOR inhibition. In this study, we demonstrate that cholesterol trafficking inhibition by itraconazole is due to direct inhibition of the lysosomal protein NPC1. We further map the binding site of itraconazole to the sterol-sensing domain of NPC1 using mutagenesis, competition with U18666A, and molecular docking. Finally, we demonstrate that simultaneous AMPK activation and cholesterol trafficking inhibition leads to synergistic inhibition of mTOR, endothelial cell proliferation, and angiogenesis.
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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.