ArticleProceedings of the National Academy of Sciences of the United States of America2015
Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 108 citations in OpenAlex.
- From fungus fighter to cancer slayer: itraconazole as a multifaceted candidate for drug-resistant prostate cancer.Prostate cancer and prostatic diseases · 2026Review
- The yeast mitochondrial porin represses Snf1/AMP kinase signaling to attenuate viral replication.Genetics · 2026Article
- Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights.RSC advances · 2026Review
- VDAC1 as prognostic marker and therapeutic target in lung adenocarcinoma: a study integrating bioinformatics and experimental validation.Discover oncology · 2025Article
- The innate immune receptor NLRX1 is a novel required modulator for mPTP opening: implications for cardioprotection.Basic research in cardiology · 2025Article
- Novel Azole-Modified Porphyrins for Mitochondria-Targeted Photodynamic Therapy.Molecules (Basel, Switzerland) · 2025Article
- Metabolic Targets in CRC: The Emerging Role of Cytochrome P450 Inhibitors.Current pharmaceutical design · 2025Review
- Exercise and nutrition benefit skeletal muscle: From influence factor and intervention strategy to molecular mechanism.Sports medicine and health science · 2024Review
- Drug Repurposing for Cancer Treatment: A Comprehensive Review.International journal of molecular sciences · 2024Review
- Article
- G6PD maintains the VSMC synthetic phenotype and accelerates vascular neointimal hyperplasia by inhibiting the VDAC1-Bax-mediated mitochondrial apoptosis pathway.Cellular & molecular biology letters · 2024Article
- Itraconazole inhibits tumor growth via CEBPB-mediated glycolysis in colorectal cancer.Cancer science · 2024Article
- The activation of the adaptor protein STING depends on its interactions with the phospholipid PI4P.Science signaling · 2024Article
- Transcriptome Analysis Reveals Distinct Patterns Between the Invasive and Noninvasive Pituitary Neuroendocrine Tumors.Journal of the Endocrine Society · 2024Article
- Combining nano-differential scanning fluorimetry and microscale thermophoresis to investigate VDAC1 interaction with small molecules.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Longitudinal diffusion barriers imposed by myofilaments and mitochondria in murine cardiac myocytes.The Journal of general physiology · 2023Article
- Article
- Mitochondria in endothelial cells angiogenesis and function: current understanding and future perspectives.Journal of translational medicine · 2023Review
- Repurposing antifungal drugs for cancer therapy.Journal of advanced research · 2023Review
- Mitochondrial Ribosomal Protein L14 Promotes Cell Growth and Invasion by Modulating Reactive Oxygen Species in Thyroid Cancer.Clinical and experimental otorhinolaryngology · 2023Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
Abstract
Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.
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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.