Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China; Department of Dermatovenereology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
J Invest Dermatol. 2019 Jul;139(7):1574-1582. doi: 10.1016/j.jid.2018.12.028. Epub 2019 Jan 25.
Infantile hemangioma is the most common benign vascular tumor of infancy. We have previously reported that itraconazole, a common antifungal agent, can clinically improve or cure infantile hemangioma; however, the underlying molecular mechanisms are still unclear. Here, we show that itraconazole treatment significantly inhibits proliferation and promotes apoptosis of the endothelial cells of mouse hemangioma cell line and infantile primary hemangioma endothelial cell. Itraconazole also remarkably reduced angiogenesis of hemangioma endothelial cell in vitro. We further performed transcriptome profiling via mRNA microarrays in hemangioma endothelial cell upon itraconazole treatment, and identified cytokine-cytokine receptor interaction as the top significantly enriched pathway. Importantly, itraconazole significantly reduced platelet-derived growth factor-D level, resulting in suppression of platelet-derived growth factor-β activation and inhibition of its downstream effectors, such as PI3K, Akt, 4E-BP1, and p70S6K, which are important for cellular growth and survival of infantile hemangioma. In conclusion, our results suggest that platelet-derived growth factor-D is a target of itraconazole in infantile hemangioma.
婴儿血管瘤是婴儿期最常见的良性血管肿瘤。我们之前曾报道过，常用抗真菌药物伊曲康唑可临床改善或治愈婴儿血管瘤；但其潜在的分子机制仍不清楚。在这里，我们发现伊曲康唑治疗可显著抑制小鼠血管瘤细胞系和婴儿原发性血管瘤内皮细胞的增殖，并促进其凋亡。伊曲康唑还可显著减少血管瘤内皮细胞的体外血管生成。我们进一步通过伊曲康唑处理后的 mRNA 微阵列进行了转录组谱分析，发现细胞因子-细胞因子受体相互作用是最显著富集的途径。重要的是，伊曲康唑可显著降低血小板衍生生长因子-D 水平，从而抑制血小板衍生生长因子-β的激活，并抑制其下游效应物，如 PI3K、Akt、4E-BP1 和 p70S6K，这些因子对于婴儿血管瘤的细胞生长和存活很重要。总之，我们的结果表明，血小板衍生生长因子-D 是伊曲康唑治疗婴儿血管瘤的靶点。
