428 Itraconazole inhibits the PDGF-D/PI3K/Akt/mTOR pathway in vitro and down-regulates serum PDGF-A of infantile hemangioma via oral administration

Abstract

The incidence of infantile hemangiomas (IHs) is 8-10% in children. We found that itraconazole, a common anti-fungal agent, can improve or cure IH for the first time. However, the underlying molecular mechanisms are still unclear. Our research showed 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 reduce angiogenesis of HemEC in vitro. We 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, p70S6K and mTOR signaling pathway, which are important for cellular growth and survival of IH. Oral itraconazole solution with 5mg/kg/d was administrated in 17 children, aging from 1 to 12 months (average 5.4 months), weighing from 5 to 10.5 kg. The blood samples collected were used to detect the concentration of serum vascular endothelial growth factor (VEGF) and PDGF-A by ELISA kits. The treatment period varied from 13 to 63 days, with total dose of itraconazole 390-2250 mg. Serum PDGF-A concentration was 52879.92 ± 31435.65 pg/mL before treatment and 26289.34 ± 26095.77 pg/mL after treatment (p<0.05), whereas VEGF showed no statistical difference (p>0.05). Both in vitro and in vivo data suggest that PDGF (at least A and D) is a novel target of itraconazole in IH, which need further investigations.