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Cited by 167Angiogenesis and VEGF in CancerCancer, Hypoxia, and MetabolismSynthesis and biological activity

Itraconazole Inhibits Angiogenesis and Tumor Growth in Non–Small Cell Lung Cancer

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Aftab, Blake T., Dobromilskaya, Irina, Liu, Jun O., Rudin, Charles M.·2011·Cancer Research
DOI 10.1158/0008-5472.can-11-0691PMC PMC3206167

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Abstract

The antiangiogenic agent bevacizumab has been approved for the treatment of non–small cell lung cancer (NSCLC), although the survival benefit associated with this agent is marginal, and toxicities and cost are substantial. A recent screen for selective inhibitors of endothelial cell proliferation identified the oral antifungal drug itraconazole as a novel agent with potential antiangiogenic activity. In this article, we define and characterize the antiangiogenic and anticancer activities of itraconazole in relevant preclinical models of angiogenesis and lung cancer. Itraconazole consistently showed potent, specific, and dose-dependent inhibition of endothelial cell proliferation, migration, and tube formation in response to both VEGF- and basic fibroblast growth factor–mediated angiogenic stimulation. In vivo, using primary xenograft models of human NSCLC, oral itraconazole showed single-agent growth-inhibitory activity associated with induction of tumor hypoxia-inducible factor 1 alpha expression and marked inhibition of tumor vascularity. Itraconazole significantly enhanced the antitumor efficacy of the chemotherapeutic agent cisplatin in the same model systems. Taken together, these data suggest that itraconazole has potent and selective inhibitory activity against multiple key aspects of tumor-associated angiogenesis in vitro and in vivo, and strongly support clinical translation of its use. Based on these observations, we have initiated a randomized phase II study comparing the efficacy of standard cytotoxic therapy with or without daily oral itraconazole in patients with recurrent metastatic NSCLC. Cancer Res; 71(21); 6764–72. ©2011 AACR.

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  • ITZ's synergistic effects with cisplatin are associated with related mechanisms in xenograft models of human lung cancer cells.

    “Its synergistic effects with cisplatin has been also associated with related mechanisms in xenograft models of human lung cancer cells.93”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [93]

    The Results section (page unavailable) reports that adding itraconazole to cisplatin significantly improved tumor-growth inhibition in two human non–small cell lung cancer xenograft models. The Discussion links the combination’s effects to findings consistent with anti-angiogenic activity. The paper does not establish that the drugs act synergistically, so that characterization exceeds its findings. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • ITZ has acceptable synergistic effects with various anticancer agents, including paclitaxel, cisplatin, and docetaxel, mainly through antiangiogenic pathways, hedgehog signaling inhibition, and effects on drug efflux pumps.

    “Accordingly, ITZ has deciphered acceptable synergistic effects with various anticancer agents, including paclitaxel, cisplatin, and docetaxel, mainly through mechanisms such as antiangiogenic pathways, hedgehog signaling inhibition, and effects on drug efflux pumps.”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [93]

    The Results section reports that adding itraconazole to cisplatin significantly improved tumor-growth inhibition in NSCLC xenografts, and the Discussion links the combination’s effects to antiangiogenic activity (page unavailable). The paper does not establish synergy with paclitaxel or docetaxel, or attribute the combination benefit to hedgehog inhibition or drug efflux pumps; hedgehog inhibition is mentioned in the Introduction as a separate prior finding. (LLM, conf=0.90)

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References 39 · Cited by 167

Research works printed but not linked: 35

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Authors
Aftab, B. T., Dobromilskaya, I., Liu, J. O., & Rudin, C. M.
Affiliations
Johns Hopkins University (US)
Corresponding author
Rudin, Charles M.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2011-10-30
Volume
71
Issue
21
Pages
6764-6772
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-11-0691
PMC
PMC3206167
OpenAlex
W2135808678
Cited by
167
References
39
Citations by year
2026: 6 · 2025: 9 · 2024: 7 · 2023: 10 · 2022: 15 · 2021: 16 · 2020: 12 · 2019: 13 · 2018: 14 · 2017: 15 · 2016: 11 · 2015: 14 · 2014: 13 · 2013: 6 · 2012: 4
FWCI
3.25
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Burroughs Wellcome Fund
  • National Cancer Institute (P50CA058184)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords
itraconazole, non-small cell lung cancer, tumor angiogenesis, angiogenesis inhibitors, endothelial cell proliferation, vascular endothelial growth factor, basic fibroblast growth factor, tumor vascularity, cisplatin combination therapy, xenograft models
MeSH terms
Adenocarcinoma, Aged, Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cell Movement, Cells, Cultured, Cisplatin, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Lung Neoplasms, Neovascularization, Pathologic, Mice, SCID, Mice, Inbred NOD, Itraconazole, Angiogenesis Inhibitors, Xenograft Model Antitumor Assays, Intercellular Signaling Peptides and Proteins, Endothelial Cells, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit

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