Drug Repurposing of Itraconazole Suppresses Angiogenesis and Hyperplasia in Port Wine Stain via Autophagy‐Apoptosis Crosstalk

Port wine stain (PWS) is a common congenital and progressive skin capillary malformation with poor clinical effects, which seriously affects the patients' appearance and social interaction. In the study, we found that itraconazole (ITRA), a common antifungal agent, showed preliminary clinical improvement in patients with PWS in our pilot observational case series; however, the underlying molecular mechanisms are still unclear. PWS pathogenesis is associated with somatic activating GNAQ R183Q mutations that constitutively activate the PI3K/AKT/mTOR pathway, and angiogenesis and fibroblast hyperplasia further play important roles in its occurrence and development. We isolated and cultured primary human umbilical vein endothelial cells (HUVECs) and PWS fibroblasts (PWSFs) by enzymatic digestion and used these cells as our cell models. In vitro, we found that ITRA inhibited proliferation, induced apoptosis, increased autophagosome formation and promoted autophagy flux of HUVECs and PWSFs. Furthermore, we explored the association between apoptosis and ITRA-induced autophagy. We found that ITRA induced autophagy, and inhibition of autophagy enhanced its pro-apoptotic and anti-proliferative effects of ITRA in PWSFs and HUVECs. In addition, ITRA may inhibit migration and angiogenesis of HUVECs by downregulating the VEGF/PI3K/AKT/mTOR signalling pathway. Together, our study presents a preliminary clinical pilot observation and a relative experimental study for the potential effects of ITRA in PWS via autophagy-apoptosis crosstalk.