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Cited by 33PI3K/AKT/mTOR signaling in cancerEsophageal Cancer Research and TreatmentHER2/EGFR in Cancer Research

Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway

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Zhang, Wei, Bhagwath, Ankur S., Ramzan, Zeeshan, Williams, Taylor A., Subramaniyan, Indhumathy, Edpuganti, Vindhya, Kallem, Raja Reddy, Dunbar, Kerry B. +16 more·2021·Molecular Cancer Therapeutics
DOI 10.1158/1535-7163.mct-20-0638PMC PMC8492513
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Abstract

Itraconazole, an FDA-approved antifungal, has antitumor activity against a variety of cancers. We sought to determine the effects of itraconazole on esophageal cancer and elucidate its mechanism of action. Itraconazole inhibited cell proliferation and induced G1-phase cell-cycle arrest in esophageal squamous cell carcinoma and adenocarcinoma cell lines. Using an unbiased kinase array, we found that itraconazole downregulated protein kinase AKT phosphorylation in OE33 esophageal adenocarcinoma cells. Itraconazole also decreased phosphorylation of downstream ribosomal protein S6, transcriptional expression of the upstream receptor tyrosine kinase HER2, and phosphorylation of upstream PI3K in esophageal cancer cells. Lapatinib, a tyrosine kinase inhibitor that targets HER2, and siRNA-mediated knockdown of HER2 similarly suppressed cancer cell growth in vitro. Itraconazole significantly inhibited growth of OE33-derived flank xenografts in mice with detectable levels of itraconazole and its primary metabolite, hydroxyitraconazole, in esophagi and tumors. HER2 total protein and phosphorylation of AKT and S6 proteins were decreased in xenografts from itraconazole-treated mice compared to xenografts from placebo-treated mice. In an early phase I clinical trial (NCT02749513) in patients with esophageal cancer, itraconazole decreased HER2 total protein expression and phosphorylation of AKT and S6 proteins in tumors. These data demonstrate that itraconazole has potent antitumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling.

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Authors
Zhang, W., Bhagwath, A. S., Ramzan, Z., Williams, T. A., Subramaniyan, I., Edpuganti, V., Kallem, R. R., Dunbar, K. B., Ding, P., Gong, K., Geurkink, S. A., Beg, M. S., Kim, J., Zhang, Q., Habib, A. A., Choi, S.-H., Lapsiwala, R., Bhagwath, G., Dowell, J. E., Melton, S. D., Jie, C., Putnam, W. C., Pham, T. H., & Wang, D. H.
Affiliations
  • Harold C. Simmons Comprehensive Cancer Center (US)
  • VA North Texas Health Care System (US)
  • Texas Christian University (US)
  • The University of Texas Southwestern Medical Center (US)
  • Texas Tech University Health Sciences Center (US)
  • Methodist Dallas Medical Center (US)
  • Baylor University Medical Center (US)
  • Des Moines University (US)
Corresponding author
Wang, David H.
ORCID
Venue
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Published
2021-08-10
Volume
20
Issue
10
Pages
1904-1915
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
DOI
10.1158/1535-7163.mct-20-0638
PMC
PMC8492513
OpenAlex
W3189374875
Cited by
33
References
49
Citations by year
2026: 7 · 2025: 8 · 2024: 4 · 2023: 5 · 2022: 9
FWCI
1.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cancer Therapeutics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • VA North Texas Health Care System
  • the U.S. Department of Veterans Affairs (5I01CX001668, 2I01BX002559–07)
  • the NIH (1R01CA196851, 1R01CA244212–01A1, R01-DK97340)
  • the Cancer Prevention Research Institute of Texas Core Facilities (RP170003)
  • the American Cancer Society (ACS-RSG-16–090–01-TBG)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Surgery › Esophageal Cancer Research and Treatment
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords
itraconazole, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, HER2, Akt signaling, phosphatidylinositol 3-kinase, ribosomal protein S6, G1 cell cycle arrest, antifungal drug repurposing, hydroxyitraconazole, lapatinib, xenografts, anticancer activity
MeSH terms
Esophageal Squamous Cell Carcinoma, Animals, Cell Cycle, Cell Movement, Esophageal Neoplasms, Female, Humans, Mice, Inbred BALB C, Mice, Nude, Prognosis, Tissue Distribution, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Apoptosis, Itraconazole, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Maximum Tolerated Dose, Xenograft Model Antitumor Assays, Cell Proliferation, Proto-Oncogene Proteins c-akt, Mice, Cytochrome P-450 CYP3A Inhibitors

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