Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis
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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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Itraconazole's cessation of cholesterol trafficking results in mTOR inhibition.
“Since mTOR signaling and proliferation in HUVEC were also inhibited by either genetically knocking down NPC1 or NPC2 or by pharmacologically inhibiting cholesterol trafficking with two other known NPC-inducing small molecules, imipramine and U18666A albeit at far higher concentrations than ITZ, it was also deciphered to cease cholesterol trafficking resulting in mTOR inhibition.26,27”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [27]
mTOR signaling and proliferation in HUVEC are inhibited by genetically knocking down NPC1 or NPC2 or by pharmacologically inhibiting cholesterol trafficking with imipramine and U18666A, albeit at far higher concentrations than itraconazole.
“Since mTOR signaling and proliferation in HUVEC were also inhibited by either genetically knocking down NPC1 or NPC2 or by pharmacologically inhibiting cholesterol trafficking with two other known NPC-inducing small molecules, imipramine and U18666A albeit at far higher concentrations than ITZ, it was also deciphered to cease cholesterol trafficking resulting in mTOR inhibition.26,27”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [27]
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- Authors
- Head, S. A., Shi, W. Q., Yang, E. J., Nacev, B. A., Hong, S. Y., Pasunooti, K. K., Li, R.-J., Shim, J. S., & Liu, J. O.
- Affiliations
- Johns Hopkins University (US)
- University of Macau (MO)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Liu, Jun O.
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-12-02
- Volume
- 12
- Issue
- 1
- Pages
- 174-182
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- PMC
- PMC5791891
- OpenAlex
- W2553764071
- Cited by
- 82
- References
- 41
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 9 · 2022: 14 · 2021: 12 · 2020: 16 · 2019: 7 · 2018: 9 · 2017: 5
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Center for Advancing Translational Sciences (UL1 TR 001079)
- National Cancer Institute (R01CA184103)
- Pharmaceutical Research and Manufacturers of America Foundation
- Flight Attendant Medical Research Institute
- Prostate Cancer Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- itraconazole, drug repurposing, antiangiogenic activity, mTOR signaling, VDAC1, NPC1, cholesterol transport, sterol-sensing domain, AMPK activation, endothelial cell proliferation, angiogenesis, lysosomal cholesterol transport, binding site mapping
- MeSH terms
- Niemann-Pick C1 Protein, Antifungal Agents, Biological Transport, Carrier Proteins, Cholesterol, Humans, Membrane Glycoproteins, Signal Transduction, Itraconazole, Angiogenesis Inhibitors, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Voltage-Dependent Anion Channel 1, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases, Human Umbilical Vein Endothelial Cells, Molecular Docking Simulation
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