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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1545243
This article is part of the Research Topic Decoding Tumor Drug Resistance: Machine Learning’s Role from Molecules to Treatment View all articles

Itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway-mediated autophagy

Provisionally accepted
Shunqiao Jin Shunqiao Jin 1,2*Xiaojiao Liu Xiaojiao Liu 1,3*Lingqin Cai Lingqin Cai 2,4*Jiayu Yan Jiayu Yan 1*Ling Li Ling Li 5*Hongjun Dong Hongjun Dong 1*Yuxue Gao Yuxue Gao 1*Xicong Zhu Xicong Zhu 2*Cong Zhang Cong Zhang 6*Xuezhu Xu Xuezhu Xu 1*
  • 1 Department of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
  • 2 Department of Dermatology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Wenzhou, China, Taizhou, China
  • 3 Department of Dermatology, Chengdu Badachu Medical Aesthetics Hospital, Chengdu, China, Chengdu, China
  • 4 Department of Dermatology, Taizhou Rehabilitation Hospital, Taizhou Enze Medical Center (Group), Taizhou, China, Taizhou, China
  • 5 Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning Province, China
  • 6 Department of Preventive Medicine, Dalian Medical University, Dalian, China, Dalian, China

The final, formatted version of the article will be published soon.

    Background: Itraconazole, 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. Method: Potential 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. Result: Using 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. Conclusion: Itraconazole induces autophagy-mediated apoptosis in melanoma cells by inhibiting Hedgehog signaling, underscoring its potential as a therapeutic option for melanoma treatment.

    Keywords: Itraconazole, Melanoma, Autophagy, Hedgehog pathway, Apoptosis, machine learning

    Received: 14 Dec 2024; Accepted: 06 Jan 2025.

    Copyright: © 2025 Jin, Liu, Cai, Yan, Li, Dong, Gao, Zhu, Zhang and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Shunqiao Jin, Department of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
    Xiaojiao Liu, Department of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
    Lingqin Cai, Department of Dermatology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Wenzhou, China, Taizhou, China
    Jiayu Yan, Department of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
    Ling Li, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning Province, China
    Hongjun Dong, Department of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
    Yuxue Gao, Department of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
    Xicong Zhu, Department of Dermatology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Wenzhou, China, Taizhou, China
    Cong Zhang, Department of Preventive Medicine, Dalian Medical University, Dalian, China, Dalian, China
    Xuezhu Xu, Department of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China

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