Itraconazole inhibits proliferation, induces apoptosis, and reduces angiogenesis of hemangioma endothelial cells by downregulating the hedgehog signaling pathway
Open accessAbstract
Infantile hemangioma (IH) is among the most prevalent benign vascular tumours in infants. The pathogenesis of IH mainly involves abnormal proliferation of vascular endothelial cells and the formation of new vessels. Itraconazole was shown to be effective in treating IH; however, the mechanism underlying its action is still unclear. The purpose of this study was to examine the effects of itraconazole on the proliferation, apoptosis, and angiogenesis of hemangioma endothelial cells (HemECs); human umbilical vein endothelial cells served as the control group. The expression of genes involved in the hedgehog (HH) signaling pathway (SHH, PTCH1, SMO, and GLI1) was determined using real-time quantitative polymerase chain reaction. Western blotting was used to determine the expression of related proteins. In this study, itraconazole significantly dose- and time-dependently inhibited the viability of HemECs. Itraconazole suppressed the expression of PCNA, Ki67, and vascular endothelial growth factor (VEGF), demonstrating that this treatment inhibited cell proliferation and angiogenesis. Moreover, itraconazole induced apoptosis of HemECs by activating the expression of BAX and inhibiting the expression of BCL2. Itraconazole inhibited SHH, PTCH1, SMO, and GLI1 expression. Activation of the HH pathway by recombinant human sonic hedgehog (rhSHH) protein attenuated the effect of itraconazole on HemECs. In conclusion, itraconazole inhibits proliferation, induces apoptosis, and reduces angiogenesis of HemECs via the downregulation of the HH signaling pathway. Therefore, itraconazole may be an alternative choice for the treatment of IH.
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ITZ decreased expression of PCNA, Ki67, and VEGF, inhibiting cell proliferation and angiogenesis in hemangioma endothelial cells.
“Inhibiting cell proliferation and angiogenesis, ITZ decreased the expression of PCNA, Ki67, and VEGF.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [90]
ITZ suppresses the hedgehog signaling system, which in turn causes apoptosis, slows proliferation, and decreases angiogenesis of hemangioma endothelial cells.
“In summary, ITZ suppresses the HH signaling system, which in turn causes apoptosis, slows proliferation, and decreases angiogenesis of HemECs.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [90]
ITZ dramatically reduced the viability of hemangioma endothelial cells in a dose- and time-dependent manner.
“ITZ dramatically reduced the viability of HemECs in this investigation in a dose- and time-dependent manner.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [90]
ITZ suppressed the expression of SHH, PTCH1, SMO, and GLI1 in hemangioma endothelial cells.
“The expression of SHH, PTCH1, SMO, and GLI1 was suppressed by ITZ.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [90]
ITZ might be a different option for treating infantile hemangioma.
“As a result, ITZ might be a different option for treating infantile hemangioma (IH).90”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [90]
ITZ caused hemangioma endothelial cells to undergo apoptosis by upregulating BAX expression and suppressing BCL2 expression.
“Furthermore, ITZ caused HemECs to undergo apoptosis by upregulating BAX expression and suppressing BCL2 expression.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [90]
ITZ's effect on hemangioma endothelial cells was lessened when rhSHH protein activated the hedgehog pathway.
“ITZ's effect on HemECs was lessened when the rhSHH protein activated 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 [90]
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- Authors
- Dong, J., Cui, J., Shi, X., Wang, T., & Liu, S.
- Affiliations
- Shandong University (CN)
- Jinan Stomatological Hospital (CN)
- Corresponding author
- Liu, Shaohua
- Venue
- Heliyon
- Publisher
- Elsevier BV
- Published
- 2023-09
- Volume
- 9
- Issue
- 9
- Pages
- e19244
- ISSN
- 2405-8440 (ISSN-L)
- PMC
- PMC10477473
- OpenAlex
- W4386052699
- Cited by
- 14
- References
- 24
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 2
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Heliyon (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Qilu Hospital of Shandong University
- Science and Technology Development Plan of Shandong Province (2019WS072)
- Medical and Health Science and Technology Development Project of Shandong Province
- Shandong University (2019–17)
- Topics
- Health Sciences › Medicine › Surgery › Vascular Malformations and Hemangiomas
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- itraconazole, infantile hemangioma, Hedgehog signaling, Sonic hedgehog, PTCH1, SMO, Gli1, endothelial cell proliferation, apoptosis, angiogenesis, vascular endothelial growth factor, Bcl2/Bax, antivascular therapy
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