Itraconazole Increases Resolvin E3 Concentration and 12/15-lipoxygenase Inhibitor Attenuates Itraconazole Cytotoxicity in Cervical Cancer Cells
Open accessAbstract
BACKGROUND/AIM: The anticancer mechanism of itraconazole remains unsolved; therefore, we studied itraconazole-induced alterations in specialized pro-resolving mediators (SPMs) in cancer cells. MATERIALS AND METHODS: The human cervical squamous carcinoma cell line CaSki was cultured with or without 1 μM itraconazole. Liquid chromatography/mass spectrometry analysis was conducted to identify SPMs that were influenced by itraconazole. Cell growth experiments were conducted using itraconazole and inhibitors targeting the metabolic pathways of candidate SPMs. RESULTS: Resolvin E3, resolvin E2, prostaglandin J2 (PGJ2), delta-12-PGJ2, and maresin 2 were identified as candidate SPMs. The 12/15-lipoxygenase inhibitor, which is involved in the conversion of 18-hydroxy-eicosapentaenoic acid to resolvin E3, attenuated the inhibitory effect of itraconazole. Inhibition of the PGJ2 metabolic pathway did not interfere with itraconazole treatment. CONCLUSION: The metabolic pathway of SPMs, including resolving E3, could be proposed as an anticancer target of itraconazole.
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The 12/15-lipoxygenase inhibitor lessened the inhibitory effect of ITZ.
“The 12/15-lipoxygenase inhibitor lessened the inhibitory effect of ITZ.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [74]
Resolvin E3 is part of the metabolic pathway of SPMs, which may be ITZ's anticancer target.
“Resolving E3 is part of the metabolic pathway of SPMs, which may be ITZ's anticancer target.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [74]
As potential SPMs, resolvin E3, resolvin E2, prostaglandin J2, delta-12-PGJ2, and maresin 2 were found.
“As potential SPMs, resolvin E3, resolvin E2, prostaglandin J2 (PGJ2), delta-12-PGJ2, and maresin 2 were found.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [74]
Treatment with ITZ was unaffected by inhibition of the PGJ2 metabolic pathway.
“Treatment with ITZ was unaffected by inhibition of the PGJ2 metabolic pathway.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [74]
Cites
Repurposing itraconazole as an anticancer agent
Tsubamoto, H., Ueda, T., Inoue, K., Sakata, K., Shibahara, H., & Sonoda, T. (2017) · Oncology Letters · doi:10.3892/ol.2017.6325 · Cited by 107 · see citing works
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Itraconazole Inhibits the Growth of Cutaneous Squamous Cell Carcinoma by Targeting HMGCS1/ACSL4 Axis
Xu, C., Zhuo, Y., Liu, Y., & Chen, H. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.828983 · Cited by 23 · see citing works
Marzi, M., Ghasemian, A., Ghanbariasad, A., Nournia, E., & Zarenezhad, E. (2026) · RSC Advances · doi:10.1039/d5ra09799a
- Authors
- ISONO, R., TSUBAMOTO, H., INOUE, K., UEDA, T., TAKIMOTO, Y., SAKATA, K., SHINOHARA, M., & SHIBAHARA, H.
- Affiliations
- Hyogo Medical University (JP)
- Kobe University (JP)
- Venue
- Anticancer Research
- Published
- 2021-09
- Volume
- 41
- Issue
- 9
- Pages
- 4271-4276
- ISSN
- 0250-7005 (ISSN-L)
- 1791-7530
- OpenAlex
- W3196345220
- Cited by
- 6
- References
- 1
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2022: 2
- FWCI
- 0.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Anticancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Hyogo College of Medicine
- Japan Society for the Promotion of Science (21K09459)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- itraconazole, specialized pro-resolving mediators, 12/15-lipoxygenase, prostaglandin J2, cervical cancer, CaSki cells, cytotoxicity, anticancer mechanism, lipid mediators
- MeSH terms
- Carcinoma, Squamous Cell, Cell Survival, Uterine Cervical Neoplasms, Chromatography, Liquid, Fatty Acids, Unsaturated, Female, Humans, Mass Spectrometry, Gene Expression Regulation, Neoplastic, Lipoxygenase Inhibitors, Itraconazole, Cell Line, Tumor, Cell Proliferation, Metabolic Networks and Pathways
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