Itraconazole induces regression of infantile hemangioma via down-regulation of the PDGF-D/PI3K/Akt/mTOR pathway

Abstract Infantile hemangioma (IH) is the most common benign vascular tumor of infancy. We have previously reported that itraconazole, a common anti-fungal agent, can clinically improve or cure IH; however, the underlying molecular mechanisms are still unclear. Here, we show that itraconazole treatment significantly inhibits the proliferation and promotes apoptosis of the endothelial cells of mouse hemangioma (EOMA) cell line and infantile primary hemangioma endothelial cell (HemEC). Itraconazole also remarkably reduced angiogenesis of HemEC in vitro . We further performed transcriptome profiling via mRNA microarrays in HemEC cells upon itraconazole treatment, and identified cytokine-cytokine receptor interaction as the top significantly enriched pathway. Importantly, itraconazole significantly reduced platelet-derived growth factor D (PDGF-D) level, resulting in suppression of PDGFR-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 IH. In conclusion, our results suggest that PDGF-D is a target of itraconazole in IH.