Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells
Open accessAbstract
Significance: Tumors promote angiogenesis to facilitate their growth and metastasis; thus, inhibition of angiogenesis is a promising strategy for treating cancer. During angiogenesis, endothelial cells (EC) are stimulated by proangiogenic factors to proliferate and migrate, leading to the formation of new blood vessels. Understanding the mechanisms regulating EC function therefore is essential for the development of new antiangiogenic interventions. Here, we identify a novel mechanism of EC regulation by the recently discovered angiogenesis inhibitor itraconazole, mediated by direct binding to the mitochondrial protein voltage-dependent anion channel 1 (VDAC1). VDAC1 inhibition perturbs mitochondrial ATP production, leading to activation of the AMP-activated protein kinase pathway and subsequent inhibition of mechanistic target of rapamycin, a regulator of EC proliferation. This study suggests VDAC1 may serve as a new therapeutic target for angiogenesis inhibition.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Itraconazole indirectly suppresses mTOR signaling via the 5′ AMP-dependent protein kinase (AMPK) in its antiangiogenic action.
“An investigation into the molecular mechanism of ITZ's antiangiogenic action found that ITZ indirectly suppresses mTOR signaling via the 5′ AMP-dependent protein kinase (AMPK), another upstream regulatory kinase.24”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [24]
Cites
In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector
Naldini, L., Blömer, U., Gallay, P., Ory, D., Mulligan, R., Gage, F. H., Verma, I. M., & Trono, D. (1996) · Science · doi:10.1126/science.272.5259.263 · Cited by 4,903 · see citing works
A public genome-scale lentiviral expression library of human ORFs
Yang, X., Boehm, J. S., Yang, X., Salehi-Ashtiani, K., Hao, T., Shen, Y., Lubonja, R., Thomas, S. R., Alkan, O., Bhimdi, T., et al. (2011) · Nature Methods · doi:10.1038/nmeth.1638 · Cited by 570 · see citing works
Pereira, G. C., Branco, A. F., Matos, J. A. C., Pereira, S. L., Parke, D., Perkins, E. L., Serafim, T. L., Sardão, V. A., Santos, M. S., Moreno, A. J. M., et al. (2007) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.128017 · Cited by 152 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Repurposing itraconazole as an anticancer agent
Tsubamoto, H., Ueda, T., Inoue, K., Sakata, K., Shibahara, H., & Sonoda, T. (2017) · Oncology Letters · doi:10.3892/ol.2017.6325 · Cited by 107 · see citing works
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. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.6b00849 · Cited by 82 · see citing works
Self-citationLiang, G., Liu, M., Wang, Q., Shen, Y., Mei, H., Li, D., & Liu, W. (2017) · Oncotarget · doi:10.18632/oncotarget.15324 · Cited by 78 · see citing works
Ou, H., Chou, W., Chu, P., Hsieh, P., Hung, C., & Tsai, K. (2019) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201801353 · Cited by 41 · see citing works
Marastoni, S., Madariaga, A., Pesic, A., Nair, S. N., Li, Z. J., Shalev, Z., Ketela, T., Colombo, I., Mandilaras, V., Cabanero, M., et al. (2022) · Cancer Research Communications · doi:10.1158/2767-9764.crc-22-0037 · Cited by 19 · see citing works
Dong, J., Cui, J., Shi, X., Wang, T., & Liu, S. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e19244 · Cited by 14 · see citing works
Kast, R. E. (2024) · Cells · doi:10.3390/cells13141175 · Cited by 4 · see citing works
Marzi, M., Ghasemian, A., Ghanbariasad, A., Nournia, E., & Zarenezhad, E. (2026) · RSC Advances · doi:10.1039/d5ra09799a
- Authors
- Head, S. A., Shi, W., Zhao, L., Gorshkov, K., Pasunooti, K., Chen, Y., Deng, Z., Li, R.-J., Shim, J. S., Tan, W., Hartung, T., Zhang, J., Zhao, Y., Colombini, M., & Liu, J. O.
- Affiliations
- Johns Hopkins University (US)
- University of Chicago (US)
- University of Maryland, College Park (US)
- Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-12-10
- Volume
- 112
- Issue
- 52
- Pages
- E7276-85
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4703001
- OpenAlex
- W2191212519
- Cited by
- 111
- References
- 3
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 12 · 2023: 10 · 2022: 13 · 2021: 9 · 2020: 10 · 2019: 15 · 2018: 12 · 2017: 12 · 2016: 4
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- Funders
- HHS | NIH | National Cancer Institute (R01CA184103)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- itraconazole, VDAC1, mTOR signaling, AMPK, endothelial cells, angiogenesis inhibition, mitochondrial metabolism, mitochondrial outer membrane, erastin, azole antifungals, drug repurposing, HUVEC proliferation, AMP/ATP ratio
- MeSH terms
- Animals, Antifungal Agents, Cells, Cultured, Enzyme Activation, HeLa Cells, Humans, Microscopy, Fluorescence, Mitochondrial Swelling, Phosphorylation, Signal Transduction, Rats, Sprague-Dawley, Itraconazole, Fluorescence Resonance Energy Transfer, RNA Interference, Cell Line, Tumor, Cell Proliferation, Voltage-Dependent Anion Channel 1, AMP-Activated Protein Kinases, HEK293 Cells, TOR Serine-Threonine Kinases, Human Umbilical Vein Endothelial Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
