Itraconazole Repolarizes Tumor-associated Macrophages and Suppresses Cervical Cancer Cell Growth
Open accessAbstract
Background/Aim: Itraconazole (ITZ), an antifungal agent, has been reported to have anti-tumor effects in patients with multiple cancer types. We investigated the involvement of tumor-associated macrophages (TAMs) in its tumor-agnostic mechanism. Materials and Methods: M1 and M2 macrophages were established from human monocyte leukemia cell line (THP-1) and their phenotypes were determined morphologically. Cell membrane antigens and secreted proteins were evaluated by western blots and enzyme-linked immunosorbent assay, respectively. The proteomic profiling of cells was done by liquid chromatography with tandem mass spectrometry and analyzed. Viability of cervical cancer cells (CaSki) was evaluated after addition of the supernatant of M2 macrophages and during co-culture with M2 macrophages, with or without 10−5 M ITZ. Results: Co-culture of M1 macrophages inhibited the proliferation of CaSki cells (p=0.012), while that of M2 macrophages promoted their proliferation (p<0.0001). After treatment of M2 macrophages with ITZ for 24 h, they changed into M1-like shape with decreased expression of cluster of differentiation 163 (CD163) and chemokine ligand 18 (CCL18). The M1-like shape was maintained for 7 weeks of ITZ treatment and reverted to original after ITZ removal. Proteomic analysis of ITZ treated-M2 macrophages also demonstrated M1-like signature including the elevated levels of tumor necrosis factor (TNF)-related proteins. After treatment with ITZ, both the supernatant of the M2 macrophages and the co-culture with M2 macrophages significantly inhibited the proliferation of CaSki cells (each, p<0.0001). Conclusion: ITZ repolarized M2 macrophages to M1 type and suppressed cervical cancer cell growth demonstrating TAM-mediated anti-cancer activity of ITZ.
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For seven weeks throughout ITZ treatment, the M1-like shape persisted, and following ITZ removal, it returned to its normal state.
“For seven weeks throughout the ITZ treatment, the M1-like shape persisted, and following ITZ removal, it returned to its normal state.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [77]
ITZ exhibited TAM-mediated anti-cancer efficacy by suppressing cervical cancer cell proliferation and repolarizing M2 macrophages to M1 type.
“ITZ exhibited TAM-mediated anti-cancer efficacy by suppressing cervical cancer cell proliferation and repolarizing M2 macrophages to M1 type.77”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [77]
After receiving ITZ for 24 hours, M2 macrophages transformed into M1-like cells and showed reduced expression of CCL18 and CD163.
“After receiving ITZ for 24 hours, M2 macrophages transformed into M1-like cells and showed reduced expression of chemokine ligand 18 (CCL18) and cluster of differentiation 163 (CD163).”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [77]
Following ITZ treatment, CaSki cell growth was strongly decreased by both the M2 macrophage supernatant and the co-culture with M2 macrophages (each, p < 0.0001).
“Following ITZ treatment, CaSki cell growth was strongly decreased by both the M2 macrophage supernatant and the co-culture with M2 macrophages (each, p < 0.0001).”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [77]
Proteomic examination of M2 macrophages treated with ITZ revealed an M1-like signature, including increased amounts of proteins linked to TNF.
“Proteomic examination of M2 macrophages treated with ITZ also revealed an M1-like signature, including increased amounts of proteins linked to tumor necrosis factor (TNF).”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [77]
M1 macrophage co-culture decreased CaSki cell proliferation (p = 0.012), but M2 macrophage co-culture increased CaSki cell proliferation (p < 0.0001).
“M1 macrophage co-culture decreased CaSki cell proliferation (p = 0.012), but M2 macrophage co-culture increased CaSki cell proliferation (p < 0.0001).”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [77]
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- Authors
- TAKIMOTO, Y., TSUBAMOTO, H., TANIGUCHI, R., SAKATA, K., TAKADA, Y., ADACHI, J., TOMONAGA, T., UEDA, T., NAKAGAWA, K., NARITA, S., WAKIMOTO, Y., & SHIBAHARA, H.
- Affiliations
- Hyogo Medical University (JP)
- National Institute of Biomedical Innovation, Health and Nutrition (JP)
- Venue
- Anticancer Research
- Published
- 2023-01-25
- Volume
- 43
- Issue
- 2
- Pages
- 569-580
- ISSN
- 0250-7005 (ISSN-L)
- 1791-7530
- OpenAlex
- W4317941520
- Cited by
- 12
- References
- 0
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 2
- FWCI
- 1.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Anticancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (21K09459)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- itraconazole, tumor-associated macrophages, macrophage polarization, M2 macrophages, M1 macrophages, cervical cancer, CaSki cells, CD163, CCL18, macrophage proteome, antifungal drug repurposing
- MeSH terms
- Tumor-Associated Macrophages, Cell Differentiation, Uterine Cervical Neoplasms, Female, Humans, Macrophages, Itraconazole, Proteomics, Cell Line, Tumor
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