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Cited by 346Hedgehog Signaling Pathway StudiesGlioma Diagnosis and TreatmentWnt/β-catenin signaling in development and cancer

Itraconazole and Arsenic Trioxide Inhibit Hedgehog Pathway Activation and Tumor Growth Associated with Acquired Resistance to Smoothened Antagonists

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Kim, James, Aftab, Blake T., Tang, Jean Y., Kim, Daniel, Lee, Alex H., Rezaee, Melika, Kim, Jynho, Chen, Baozhi +6 more·2013·Cancer Cell
DOI 10.1016/j.ccr.2012.11.017PMC PMC3548977
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Abstract

Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors. Leading inhibitors in clinical development act by binding to a common site within Smoothened, a critical pathway component. Acquired Smoothened mutations, including SMO(D477G), confer resistance to these inhibitors. Here, we report that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that of current Smoothened antagonists, retain inhibitory activity in vitro in the context of all reported resistance-conferring Smoothened mutants and GLI2 overexpression. Itraconazole and arsenic trioxide, alone or in combination, inhibit the growth of medulloblastoma and basal cell carcinoma in vivo, and prolong survival of mice with intracranial drug-resistant SMO(D477G) medulloblastoma.

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  • Itraconazole suppresses the Hedgehog pathway by blocking SMO and/or GLI, particularly GLI1, and their downstream targets through a variety of mechanisms.

    “By blocking SMO and/or GLI, particularly GLI1, and their downstream targets through a variety of mechanisms, ITZ has been shown to suppress the Hh pathway.”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [42]

    The Results (section on GDC-0449-resistant SMO) show that itraconazole inhibits SMO-mediated Hedgehog activity, and the tumor Results report reduced Gli1 mRNA. But the GLI2-overexpression Results say itraconazole acts upstream of GLI2 and does not inhibit activity induced by GLI2 overexpression. The paper therefore does not establish that itraconazole directly blocks GLI, particularly GLI1, or that it does so through a variety of mechanisms. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Preclinical investigations have verified that itraconazole can treat cancer by blocking the Hedgehog pathway.

    “Furthermore, a number of preclinical investigations have verified that ITZ can treat cancer by blocking the Hh pathway41,42 (Fig. 2).”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [42]

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References 77 · Cited by 346

Research works printed but not linked: 70

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Authors
Kim, J., Aftab, B. T., Tang, J. Y., Kim, D., Lee, A. H., Rezaee, M., Kim, J., Chen, B., King, E. M., Borodovsky, A., Riggins, G. J., Epstein, E. H., Beachy, P. A., & Rudin, C. M.
Affiliations
  • Institute for Stem Cell Biology and Regenerative Medicine (US)
  • Johns Hopkins University (US)
  • Stanford University (US)
  • Howard Hughes Medical Institute (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
  • Beachy, Philip A.
  • Rudin, Charles M.
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2013-01
Volume
23
Issue
1
Pages
23-34
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccr.2012.11.017
PMC
PMC3548977
OpenAlex
W2087837366
Cited by
346
References
77
Citations by year
2026: 8 · 2025: 9 · 2024: 15 · 2023: 18 · 2022: 21 · 2021: 19 · 2020: 23 · 2019: 34 · 2018: 29 · 2017: 25 · 2016: 27 · 2015: 62 · 2014: 40 · 2013: 16
FWCI
21.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health
  • National Cancer Institute (P50CA058184)
  • National Institute of General Medical Sciences (R01GM102498)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
itraconazole, arsenic trioxide, Hedgehog signaling, Smoothened antagonists, acquired drug resistance, medulloblastoma, basal cell carcinoma, drug repurposing, combination therapy, intracranial tumor growth
MeSH terms
Smoothened Receptor, Arsenic Trioxide, Anilides, Animals, Antineoplastic Agents, Arsenicals, Basal Cell Carcinoma, Carcinoma, Basal Cell, Medulloblastoma, Oxides, Pyridines, Signal Transduction, Itraconazole, Drug Resistance, Neoplasm, Receptors, G-Protein-Coupled, Mice, Hedgehog Proteins

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