Itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway-mediated autophagy
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ITZ dramatically slowed the growth of tumors in the A375 and A2058 xenograft models in vivo.
“ITZ dramatically slowed the growth of tumors in the A375 and A2058 xenograft models in vivo.60”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [60]
SQSTM1 was found to be the main target of ITZ using the probabilistic matrix factorization machine learning algorithm.
“SQSTM1 was found to be the main target of ITZ using the probabilistic matrix factorization (PMF) machine learning algorithm.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [60]
ITZ interfered with the activation of recombinant human Sonic Hedgehog and inhibited hedgehog signaling.
“Additionally, ITZ interfered with the activation of the recombinant human Sonic Hedgehog (rhSHH), a hedgehog agonist, and inhibited hedgehog signaling.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [60]
ITZ suppressed the growth of melanoma cells by causing autophagy-mediated apoptosis and G1 phase arrest in A375 and A2058 cells.
“By causing autophagy-mediated apoptosis and G1 phase arrest in A375 and A2058 cells, ITZ suppressed the growth of melanoma cells.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [60]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Autophagy: Renovation of Cells and Tissues
Mizushima, N., & Komatsu, M. (2011) · Cell · doi:10.1016/j.cell.2011.10.026 · Cited by 6,467 · see citing works
Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery
Hennessy, B. T., Smith, D. L., Ram, P. T., Lu, Y., & Mills, G. B. (2005) · Nature Reviews Drug Discovery · doi:10.1038/nrd1902 · Cited by 2,183 · see citing works
Autophagy and autophagy-related proteins in cancer
Li, X., He, S., & Ma, B. (2020) · Molecular Cancer · doi:10.1186/s12943-020-1138-4 · Cited by 1,653 · see citing works
Schadendorf, D., van Akkooi, A. C. J., Berking, C., Griewank, K., Gutzmer, R., Hauschild, A., Stang, A., Roesch, A., & Ugurel, S. (2018) · The Lancet · doi:10.1016/s0140-6736(18)31559-9 · Cited by 1,516 · see citing works
Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis
Thayer, S. P., di Magliano, M. P., Heiser, P. W., Nielsen, C. M., Roberts, D. J., Lauwers, G. Y., Qi, Y., Gysin, S., Castillo, C. F. F.-D., Yajnik, V., et al. (2003) · Nature · doi:10.1038/nature02009 · Cited by 1,479 · see citing works
Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours
Berman, D. M., Karhadkar, S. S., Maitra, A., Oca, R. M. D., Gerstenblith, M. R., Briggs, K. J., Parker, A. R., Shimada, Y., Eshleman, J. R., Watkins, D. N., et al. (2003) · Nature · doi:10.1038/nature01972 · Cited by 1,251 · see citing works
Hedgehog: functions and mechanisms
Varjosalo, M., & Taipale, J. (2008) · Genes & Development · doi:10.1101/gad.1693608 · Cited by 1,217 · see citing works
Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion
Sousa, C. M., Biancur, D. E., Wang, X., Halbrook, C. J., Sherman, M. H., Zhang, L., Kremer, D., Hwang, R. F., Witkiewicz, A. K., Ying, H., et al. (2016) · Nature · doi:10.1038/nature19084 · Cited by 1,122 · see citing works
Heras-Sandoval, D., Pérez-Rojas, J. M., Hernández-Damián, J., & Pedraza-Chaverri, J. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.08.019 · Cited by 1,091 · see citing works
Hedgehog signalling in prostate regeneration, neoplasia and metastasis
Karhadkar, S. S., Bova, G. S., Abdallah, N., Dhara, S., Gardner, D. R., Maitra, A., Isaacs, J. T., Berman, D. M., & Beachy, P. A. (2004) · Nature · doi:10.1038/nature02962 · Cited by 950 · see citing works
Long, G. V., Swetter, S. M., Menzies, A. M., Gershenwald, J. E., & Scolyer, R. A. (2023) · The Lancet · doi:10.1016/s0140-6736(23)00821-8 · Cited by 753 · see citing works
Gli Proteins in Development and Disease
Hui, C., & Angers, S. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154048 · Cited by 693 · see citing works
Mechanisms of Hedgehog pathway activation in cancer and implications for therapy
Scales, S. J., & de Sauvage, F. J. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.03.007 · Cited by 645 · see citing works
(2000) · PubMed · Cited by 614 · see citing works
Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth
Kim, J., Tang, J. Y., Gong, R., Kim, J., Lee, J. J., Clemons, K. V., Chong, C. R., Chang, K. S., Fereshteh, M., Gardner, D., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.02.027 · Cited by 527 · see citing works
The melanoma revolution: From UV carcinogenesis to a new era in therapeutics
Lo, J. A., & Fisher, D. E. (2014) · Science · doi:10.1126/science.1253735 · Cited by 426 · see citing works
p62 in Cancer: Signaling Adaptor Beyond Autophagy
Moscat, J., Karin, M., & Díaz-Meco, M. T. (2016) · Cell · doi:10.1016/j.cell.2016.09.030 · Cited by 392 · see citing works
Autophagy as a molecular target for cancer treatment
Kocatürk, N. M., Akkoç, Y., Kığ, C., Bayraktar, O., Gözüaçık, D., & Kutlu, Ö. (2019) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2019.04.011 · Cited by 388 · see citing works
Emerging roles of ATG proteins and membrane lipids in autophagosome formation
Nishimura, T., & Tooze, S. A. (2020) · Cell Discovery · doi:10.1038/s41421-020-0161-3 · Cited by 318 · see citing works
Hedgehog Signaling: From Basic Biology to Cancer Therapy
Wu, F., Zhang, Y., Sun, B., McMahon, A. P., & Wang, Y. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.02.010 · Cited by 304 · see citing works
Kim, D. J., Kim, J., Spaunhurst, K., Montoya, J., Khodosh, R., Chandra, K., Fu, T., Gilliam, A., Molgo, M., Beachy, P. A., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2013.49.9525 · Cited by 289 · see citing works
Hedgehog signaling in tissue homeostasis, cancers and targeted therapies
Jing, J., Wu, Z., Wang, J., Luo, G., Lin, H., Fan, Y., & Zhou, C. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01559-5 · Cited by 261 · see citing works
Context-dependent Regulation of the GLI Code in Cancer by HEDGEHOG and Non-HEDGEHOG Signals
Stecca, B. A., & Altaba, A. R. I. (2010) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjp052 · Cited by 252 · see citing works
Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease
Sigafoos, A. N., Paradise, B. D., & Fernández-Zapico, M. E. (2021) · Cancers · doi:10.3390/cancers13143410 · Cited by 245 · see citing works
Activation of the hedgehog pathway in human hepatocellular carcinomas
Huang, S., He, J., Zhang, X., Bian, Y., Yang, L., Xie, G., Zhang, K., Tang, W. W., Stelter, A. A., Wang, Q., et al. (2006) · Carcinogenesis · doi:10.1093/carcin/bgi378 · Cited by 244 · see citing works
Hedgehog signaling mechanism and role in cancer
Jiang, J. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.04.003 · Cited by 220 · see citing works
Guo, H., Ding, H., Tang, X., Liang, M., Li, S., Zhang, J., & Cao, J. (2021) · Thoracic Cancer · doi:10.1111/1759-7714.13925 · Cited by 210 · see citing works
Liu, R., Li, J., Zhang, T., Zou, L., Chen, Y., Wang, K., Lei, Y., Yuan, K., Li, Y., Lan, J., et al. (2014) · Autophagy · doi:10.4161/auto.28912 · Cited by 178 · see citing works
Itraconazole Inhibits Angiogenesis and Tumor Growth in Non–Small Cell Lung Cancer
Aftab, B. T., Dobromilskaya, I., Liu, J. O., & Rudin, C. M. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0691 · Cited by 167 · see citing works
Crosstalks between inflammasome and autophagy in cancer
Chung, C., Seo, W., Silwal, P., & Jo, E. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00936-9 · Cited by 149 · see citing works
Role of Hedgehog Signaling in Breast Cancer: Pathogenesis and Therapeutics
Galdo, N. A. R., Montero, Á. L., & Wertheimer, E. V. (2019) · Cells · doi:10.3390/cells8040375 · Cited by 142 · see citing works
The cellular decision between apoptosis and autophagy
Fan, Y., & Zong, W. (2012) · 癌症：英文版 · doi:10.5732/cjc.012.10106 · Cited by 141 · see citing works
Goh, V., Halligan, S., Daley, F. M., Wellsted, D. M., Guenther, T., & Bartram, C. I. (2008) · Radiology · doi:10.1148/radiol.2492071365 · Cited by 131 · see citing works
Wang, X., Wei, S., Zhao, Y., Shi, C., Liu, P., Zhang, C., Lei, Y., Zhang, B., Bai, B., Huang, Y., et al. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.10.034 · Cited by 108 · see citing works
Self-citationde Macedo-Silva, S. T., Urbina, J. A., de Souza, W., & Rodrigues, J. C. F. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083247 · Cited by 106 · see citing works
Itraconazole exerts anti-liver cancer potential through the Wnt, PI3K/AKT/mTOR, and ROS pathways
Wang, W., Dong, X., Liu, Y., Ni, B., Sai, N., You, L., Sun, M., Yao, Y., Qu, C., Yin, X., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110661 · Cited by 105 · see citing works
Ally, M. S., Ransohoff, K. J., Sarin, K. Y., Atwood, S. X., Rezaee, M., Bailey, I., Kim, J., Beachy, P. A., Chang, A. L. S., Oro, A. E., et al. (2016) · JAMA Dermatology · doi:10.1001/jamadermatol.2015.5473 · Cited by 93 · see citing works
Liang, G., Liu, M., Wang, Q., Shen, Y., Mei, H., Li, D., & Liu, W. (2017) · Oncotarget · doi:10.18632/oncotarget.15324 · Cited by 78 · see citing works
Sun, Y., Huang, Y., Huang, F., Mei, W.-L., Liu, Q., Wang, C.-C., Lin, Y., Huang, C., Li, Y., Dai, H., et al. (2018) · Theranostics · doi:10.7150/thno.23304 · Cited by 75 · see citing works
Repurposing itraconazole for the treatment of cancer
Pounds, R., Leonard, S. M., Dawson, W. O., & Kehoe, S. T. (2017) · Oncology Letters · doi:10.3892/ol.2017.6569 · Cited by 67 · see citing works
Hedgehog signaling in skin cancers
Li, C., Chi, S., & Xie, J. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.03.002 · Cited by 64 · see citing works
Hu, Q., Hou, Y.-C., Huang, J., Fang, J.-Y., & Xiong, H. (2017) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-017-0526-0 · Cited by 63 · see citing works
Zhang, W., Bhagwath, A. S., Ramzan, Z., Williams, T. A., Subramaniyan, I., Edpuganti, V., Kallem, R. R., Dunbar, K. B., Ding, P., Gong, K., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0638 · Cited by 33 · see citing works
Apalla, Z., Papageorgiou, C., Lallas, A., Sotiriou, E., Lazaridou, E., Vakirlis, E., Kyrgidis, Α., & Ioannides, D. (2017) · Clinical Cosmetic and Investigational Dermatology · doi:10.2147/ccid.s101330 · Cited by 29 · see citing works
Klein, S. D., Nguyen, D. C., Bhakta, V., Wong, D. A., Chang, V. Y., Davidson, T. B., & Martínez-Agosto, J. A. (2019) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.61368 · Cited by 29 · see citing works
Chen, K., Cheng, L., Qian, W., Jiang, Z., Sun, L., Zhao, Y., Zhou, Y., Zhao, L., Wang, P., Duan, W., et al. (2018) · Oncology Reports · doi:10.3892/or.2018.6281 · Cited by 24 · see citing works
Intratumoral therapies and in-situ vaccination for melanoma
Huppert, L. A., & DAUD, A. I. (2022) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2021.1890512 · Cited by 24 · see citing works
Smith, C. C., Lee, K. S., Li, B., Laing, J. M., Hersl, J., Shvartsbeyn, M., & Aurelian, L. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.108 · Cited by 23 · see citing works
Shen, P.-W., Chou, Y.-M., Li, C.-L., Liao, E.-C., Huang, H.-S., Yin, C.-H., Chen, C.-L., & Yu, S.-J. (2021) · Oncology Letters · doi:10.3892/ol.2021.13029 · Cited by 23 · see citing works
The Sonic Hedgehog signaling pathway regulates autophagy and migration in ovarian cancer
Pan, Y., Zhou, J., Zhang, W., Yan, L., Lu, M., Dai, Y., Zhou, H., Zhang, S., & Yang, J. (2021) · Cancer Medicine · doi:10.1002/cam4.4018 · Cited by 18 · see citing works
Inoue, K., Tsubamoto, H., Isono‐Nakata, R., Sakata, K., & Nakagomi, N. (2018) · BMC Cancer · doi:10.1186/s12885-018-4520-5 · Cited by 16 · see citing works
Li, L., Wang, X., Jiang, M., Li, L., Wang, D., & Li, Y. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117420 · Cited by 10 · see citing works
Self-citationThe Effects of Hedgehog Signaling Pathway on the Proliferation and Apoptosis of Melanoma Cells
Peng, Z.-P., Huang, S.-F., Li, J., Tang, X., Wang, X.-Y., & Li, H. (2022) · Journal of Oncology · doi:10.1155/2022/4984866 · Cited by 10 · see citing works
Sun, Y., Fang, Q., Liu, W., Liu, Y., & Zhang, C. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05926-6 · Cited by 10 · see citing works
Self-citationCai, L., Du, X., Zhang, C., Yu, S., Liu, L., Zhao, J., Zhao, Y., Zhang, C., Wu, J., Wang, B., et al. (2021) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-021-03095-z · Cited by 6 · see citing works
Self-citationPerturbations to the Hedgehog Pathway in Sea Urchin Embryos
Warner, J. F., & McClay, D. R. (2014) · Methods in molecular biology · doi:10.1007/978-1-62703-974-1_14 · Cited by 6 · see citing works
Flagged first, then by citations
1 of the 57 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Repurposing Itraconazole in Combination with Chemotherapy and Immune Checkpoint Inhibitor for Cancer
Zonfa, C. E., Thyagarajan‐Sahu, A., & Sahu, R. P. (2026) · Medical Sciences · doi:10.3390/medsci14010055 · Cited by 3 · see citing works
Marzi, M., Ghasemian, A., Ghanbariasad, A., Nournia, E., & Zarenezhad, E. (2026) · RSC Advances · doi:10.1039/d5ra09799a
Богданова, В. А., Спирина, Л. В., Chizhevskaya, S. Y., & Nikulnikov, K. V. (2025) · Kazan medical journal · doi:10.17816/kmj653373
Souza, L. O., Papoutsi, D. G., & Moreira, J. M. A. (2025) · Prostate Cancer and Prostatic Diseases · doi:10.1038/s41391-026-01142-3
- Authors
- Jin, S., Liu, X., Cai, L., Yan, J., Li, L., Dong, H., Gao, Y., Zhu, X., Zhang, C., & Xu, X.
- Affiliations
- Dalian Medical University (CN)
- Wenzhou Medical University (CN)
- Affiliated Zhongshan Hospital of Dalian University (CN)
- Corresponding author
- Zhang, Cong
- Xu, Xuezhu
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2025-01-23
- Volume
- 16
- Pages
- 1545243-1545243
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC11798931
- OpenAlex
- W4406774835
- Cited by
- 4
- References
- 57
- Citations by year
- 2026: 2 · 2025: 2
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Department of Science and Technology of Liaoning Province (2021JH1 / 10400051, 2021JH1)
- Science and Technology Plan Project of Taizhou
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- itraconazole, melanoma, apoptosis, autophagy, Hedgehog signaling, Sonic hedgehog, p62, G1 cell cycle arrest, antifungal drug repurposing, tumor xenografts, A375 cells, A2058 cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
