Itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway-mediated autophagy
BackgroundItraconazole, a widely used antifungal medication, has shown potential in inhibiting tumor growth and reducing angiogenesis. However, its role in melanoma tumor growth remains insufficiently explored. This study investigates the inductive effect of itraconazole on autophagy-mediated apopto...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1545243/full |
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| author | Shunqiao Jin Shunqiao Jin Xiaojiao Liu Xiaojiao Liu Lingqin Cai Lingqin Cai Jiayu Yan Ling Li Hongjun Dong Yuxue Gao Xicong Zhu Cong Zhang Xuezhu Xu |
| author_facet | Shunqiao Jin Shunqiao Jin Xiaojiao Liu Xiaojiao Liu Lingqin Cai Lingqin Cai Jiayu Yan Ling Li Hongjun Dong Yuxue Gao Xicong Zhu Cong Zhang Xuezhu Xu |
| author_sort | Shunqiao Jin |
| collection | DOAJ |
| description | BackgroundItraconazole, a widely used antifungal medication, has shown potential in inhibiting tumor growth and reducing angiogenesis. However, its role in melanoma tumor growth remains insufficiently explored. This study investigates the inductive effect of itraconazole on autophagy-mediated apoptosis in melanoma cells.MethodPotential drug targets were identified using the PMF machine learning algorithm. Apoptosis and cell cycle in melanoma cell lines A375 and A2058 were assessed via flow cytometry. Western blot analysis was performed to examine autophagy and associated signaling proteins, while autophagy flux and autophagosome formation were visualized using fluorescence microscopy. A melanoma cell xenograft mouse model was established to evaluate the inhibitory mechanisms of itraconazole on tumor cell proliferation.ResultUsing the PMF machine learning algorithm, SQSTM1 was identified as the primary target of itraconazole. Itraconazole inhibited melanoma cell proliferation by inducing G1 phase arrest and autophagy-mediated apoptosis in A375 and A2058 cells. Furthermore, itraconazole suppressed Hedgehog signaling and counteracted the activation of the Hedgehog agonist recombinant human Sonic Hedgehog (rhShh). In vivo, itraconazole significantly reduced tumor growth in A375 and A2058 xenograft models.ConclusionItraconazole induces autophagy-mediated apoptosis in melanoma cells by inhibiting Hedgehog signaling, underscoring its potential as a therapeutic option for melanoma treatment. |
| format | Article |
| id | doaj-art-4d6948ae0fab4a75ab2b7c4e07cd5343 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-4d6948ae0fab4a75ab2b7c4e07cd53432025-01-23T06:56:18ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011610.3389/fphar.2025.15452431545243Itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway-mediated autophagyShunqiao Jin0Shunqiao Jin1Xiaojiao Liu2Xiaojiao Liu3Lingqin Cai4Lingqin Cai5Jiayu Yan6Ling Li7Hongjun Dong8Yuxue Gao9Xicong Zhu10Cong Zhang11Xuezhu Xu12Department of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Dermatology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, ChinaDepartment of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Dermatology, Chengdu Badachu Medical Aesthetics Hospital, Chengdu, ChinaDepartment of Dermatology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, ChinaDepartment of Dermatology, Taizhou Rehabilitation Hospital, Taizhou Enze Medical Center (Group), Taizhou, ChinaDepartment of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Dermatology, The Affiliated Zhongshan Hospital of Dalian University, Dalian, ChinaDepartment of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Dermatology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, ChinaDepartment of Preventive Medicine, Dalian Medical University, Dalian, ChinaDepartment of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, ChinaBackgroundItraconazole, a widely used antifungal medication, has shown potential in inhibiting tumor growth and reducing angiogenesis. However, its role in melanoma tumor growth remains insufficiently explored. This study investigates the inductive effect of itraconazole on autophagy-mediated apoptosis in melanoma cells.MethodPotential drug targets were identified using the PMF machine learning algorithm. Apoptosis and cell cycle in melanoma cell lines A375 and A2058 were assessed via flow cytometry. Western blot analysis was performed to examine autophagy and associated signaling proteins, while autophagy flux and autophagosome formation were visualized using fluorescence microscopy. A melanoma cell xenograft mouse model was established to evaluate the inhibitory mechanisms of itraconazole on tumor cell proliferation.ResultUsing the PMF machine learning algorithm, SQSTM1 was identified as the primary target of itraconazole. Itraconazole inhibited melanoma cell proliferation by inducing G1 phase arrest and autophagy-mediated apoptosis in A375 and A2058 cells. Furthermore, itraconazole suppressed Hedgehog signaling and counteracted the activation of the Hedgehog agonist recombinant human Sonic Hedgehog (rhShh). In vivo, itraconazole significantly reduced tumor growth in A375 and A2058 xenograft models.ConclusionItraconazole induces autophagy-mediated apoptosis in melanoma cells by inhibiting Hedgehog signaling, underscoring its potential as a therapeutic option for melanoma treatment.https://www.frontiersin.org/articles/10.3389/fphar.2025.1545243/fullitraconazolemelanomaautophagyhedgehog pathwayapoptosismachine learning |
| spellingShingle | Shunqiao Jin Shunqiao Jin Xiaojiao Liu Xiaojiao Liu Lingqin Cai Lingqin Cai Jiayu Yan Ling Li Hongjun Dong Yuxue Gao Xicong Zhu Cong Zhang Xuezhu Xu Itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway-mediated autophagy Frontiers in Pharmacology itraconazole melanoma autophagy hedgehog pathway apoptosis machine learning |
| title | Itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway-mediated autophagy |
| title_full | Itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway-mediated autophagy |
| title_fullStr | Itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway-mediated autophagy |
| title_full_unstemmed | Itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway-mediated autophagy |
| title_short | Itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway-mediated autophagy |
| title_sort | itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway mediated autophagy |
| topic | itraconazole melanoma autophagy hedgehog pathway apoptosis machine learning |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1545243/full |
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