The anti-cancer effects of itraconazole in epithelial ovarian cancer
Open accessAbstract
We assessed the anti-proliferative activity of itraconazole using an EOC cell line (SKOV3ip1) and endothelial cell lines (HUVEC & SVEC4-10). We also examined angiogenesis (VEGFR2, p-ERK, p-PLCr1/2), hedgehog (Gli1, Ptch1, SMO), and mTOR (pS6K1) signaling pathways to determine the mechanism of action of itraconazole. Furthermore, we evaluated the synergistic effects of itraconazole and paclitaxel using orthotopic mouse models with established EOC cells (SKOV3ip1 or HeyA8) as well as patient-derived xenografts (PDXs). Itraconazole treatment inhibited proliferation of endothelial cells in a dose-dependent manner, but had no effect on EOC cells. The endothelial cell antiproliferative effect was associated with inhibition of hedgehog, and mTOR pathways and angiogenesis. In xenograft models of EOC using SKOV3ip1 or HeyA8, mice treated with the combination of itraconazole and paclitaxel had significantly decreased tumor weight than the control, paclitaxel-alone, or itraconazole-alone groups. Tissue derived from these tumors had significantly lower microvessel density than tissue from the other groups as well as hedgehog and mTOR pathway inhibition. We confirmed those effects in two EOC PDX models. These results suggest that itraconazole selectively inhibits endothelial cells rather than cancer cells by targeting multiple pathways including hedgehog, and mTOR pathways and angiogenesis.
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ITZ's synergistic effects with paclitaxel against ovarian cancer cells are via antiangiogenic and hedgehog signaling mechanisms.
“Its synergistic effects with paclitaxel has been via these mechanisms against ovarian cancer cells.92”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [92]
The Results report that itraconazole plus paclitaxel reduced ovarian tumor growth in mouse models, alongside reduced tumor vasculature and hedgehog-signaling markers. The Discussion, however, says itraconazole did not inhibit ovarian cancer cell proliferation in vitro and suggests its effect is on endothelial cells rather than cancer cells themselves. Thus the proposed mechanisms are supported for tumor effects, but not as a demonstrated direct effect against ovarian cancer cells. (LLM, conf=0.88)
Experimental — accuracy not yet measuredITZ 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 [92]
The Results and Discussion report synergy between itraconazole and paclitaxel in ovarian-cancer mouse models, alongside reduced angiogenesis and hedgehog-signaling markers (page unavailable). Our copy does not support synergy with cisplatin or docetaxel, or a role for drug efflux pumps; searches for those terms returned no matching passage. (LLM, conf=0.88)
Experimental — accuracy not yet measuredITZ has demonstrated various effects on the efficacy of anticancer drugs and has been considered as an adjuvant in cancer therapy.
“ITZ, participating in various signaling circuits such as antiangiogenic effects (VEGFR and mTOR pathways) and hedgehog signaling pathway inhibition, has demonstrated various effects on the efficacy of anticancer drugs and has been considered as an adjuvant in cancer therapy.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [92]
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References 28 · Cited by 53
Research works printed but not linked: 23
- [1]Jemal A Siegel R Xu J Ward E Cancer statistics, 2010 CA Cancer J Clin 2010 60 277 300 10.3322/caac.20073 20610543 · DOI · Paper page
- [2]Yancik R Ovarian cancer. Age contrasts in incidence, histology, disease stage at diagnosis, and mortality Cancer 1993 71 517 523 10.1002/cncr.2820710205 8420671 · DOI
- [3]Aftab BT Dobromilskaya I Liu JO Rudin CM Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer Cancer Res 2011 71 6764 6772 10.1158/0008-5472.CAN-11-0691 21896639 PMC3206167 · DOI · Paper page
- [4]Chong CR Inhibition of angiogenesis by the antifungal drug itraconazole ACS Chem Biol 2007 2 263 270 10.1021/cb600362d 17432820 · DOI · Paper page
- [5]Nacev BA Grassi P Dell A Haslam SM Liu JO The antifungal drug itraconazole inhibits vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, trafficking, and signaling in endothelial cells J Biol Chem 2011 286 44045 44056 10.1074/jbc.M111.278754 22025615 PMC3243534 · DOI
- [6]Xu J Dang Y Ren YR Liu JO Cholesterol trafficking is required for mTOR activation in endothelial cells Proc Natl Acad Sci U S A 2010 107 4764 4769 10.1073/pnas.0910872107 20176935 PMC2842052 · DOI · Paper page
- [7]Karhadkar SS Hedgehog signalling in prostate regeneration, neoplasia and metastasis Nature 2004 431 707 712 10.1038/nature02962 15361885 · DOI
- [8]Ally MS Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma JAMA Dermatol 2016 152 452 456 10.1001/jamadermatol.2015.5473 26765315 PMC4833646 · DOI
- [9]Burger RA Incorporation of bevacizumab in the primary treatment of ovarian cancer N Engl J Med 2011 365 2473 2483 10.1056/NEJMoa1104390 22204724 · DOI
- [10]Perren TJ A phase 3 trial of bevacizumab in ovarian cancer N Engl J Med 2011 365 2484 2496 10.1056/NEJMoa1103799 22204725 · DOI
- [11]Kim J Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth Cancer Cell 2010 17 388 399 10.1016/j.ccr.2010.02.027 20385363 PMC4039177 · DOI · Paper page
- [12]Berton-Rigaud D Gynecologic Cancer InterGroup (GCIG) consensus review for uterine and ovarian carcinosarcoma Int J Gynecol Cancer 2014 24 S55 60 10.1097/IGC.0000000000000228 25341582 · DOI
- [14]Paley PJ Vascular endothelial growth factor expression in early stage ovarian carcinoma Cancer 1997 80 98 106 10.1002/(SICI)1097-0142(19970701)80:1<98::AID-CNCR13>3.0.CO;2-A 9210714 · DOI
- [15]Hartenbach EM Vascular endothelial growth factor (VEGF) expression and survival in human epithelial ovarian carcinomas Cancer Lett 1997 121 169 175 10.1016/S0304-3835(97)00350-9 9570355 · DOI
- [16]Cohn DE Kim KH Resnick KE O’Malley DM Straughn JM Jr. At what cost does a potential survival advantage of bevacizumab make sense for the primary treatment of ovarian cancer? A cost-effectiveness analysis J Clin Oncol 2011 29 1247 1251 10.1200/JCO.2010.32.1075 21383297 · DOI
- [17]Suh DH Lee KH Kim K Kang S Kim JW Major clinical research advances in gynecologic cancer in 2014 J Gynecol Oncol 2015 26 156 167 10.3802/jgo.2015.26.2.156 25872896 PMC4397233 · DOI
- [18]Tsubamoto H Sonoda T Yamasaki M Inoue K Impact of combination chemotherapy with itraconazole on survival of patients with refractory ovarian cancer Anticancer Res 2014 34 2481 2487 24778064
- [19]Tsubamoto H Combination Chemotherapy with Itraconazole for Treating Metastatic Pancreatic Cancer in the Second-line or Additional Setting Anticancer Res 2015 35 4191 4196 26124377
- [20]Aliev G Li Y Palacios HH Obrenovich ME Oxidative stress induced mitochondrial DNA deletion as a hallmark for the drug development in the context of the cerebrovascular diseases Recent Pat Cardiovasc Drug Discov 2011 6 222 241 10.2174/157489011797376942 21906026 · DOI
- [21]Halliwell B Oxygen radicals as key mediators in neurological disease: fact or fiction? Ann Neurol 1992 32 Suppl S10 15 10.1002/ana.410320704 1510365 · DOI
- [22]Desouki MM Kulawiec M Bansal S Das GM Singh KK Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors Cancer Biol Ther 2005 4 1367 1373 10.4161/cbt.4.12.2233 16294028 · DOI
- [24]Lee CH Establishment of subrenal capsule xenografts of primary human ovarian tumors in SCID mice: potential models Gynecol Oncol 2005 96 48 55 10.1016/j.ygyno.2004.09.025 15589579 · DOI
- [25]Lee JW Sphingosine kinase 1 as a potential therapeutic target in epithelial ovarian cancer Int J Cancer 2015 137 221 229 10.1002/ijc.29362 25429856 · DOI
- Authors
- Choi, C. H., Ryu, J.-Y., Cho, Y.-J., Jeon, H.-K., Choi, J.-J., Ylaya, K., Lee, Y.-Y., Kim, T.-J., Chung, J.-Y., Hewitt, S. M., Kim, B.-G., Bae, D.-S., & Lee, J.-W.
- Affiliations
- Samsung Medical Center (KR)
- National Institutes of Health (US)
- Corresponding author
- Lee, Jeong-Won
- ORCID
- Venue
- Scientific Reports
- Published
- 2017-07-26
- Volume
- 7
- Issue
- 1
- Pages
- 6552-6552
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5529373
- OpenAlex
- W2737650285
- Cited by
- 53
- References
- 28
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 7 · 2021: 7 · 2020: 10 · 2019: 8 · 2018: 5
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Korea Health Industry Development Institute (HI14C1940, HI14C3418)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- itraconazole, epithelial ovarian cancer, endothelial cell proliferation, angiogenesis, Hedgehog signaling, mTOR signaling, VEGFR2, paclitaxel combination therapy, patient-derived xenografts, microvessel density, HeyA8 cells, drug repurposing
- MeSH terms
- Carcinoma, Ovarian Epithelial, Animals, Antineoplastic Agents, Disease Models, Animal, Drug Synergism, Female, Neoplasm Transplantation, Treatment Outcome, Paclitaxel, Itraconazole, Endothelial Cells, Cell Proliferation, Mice, Heterografts
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