Naphthoquinones from Handroanthus impetiginosus promote skin wound healing through Sirt3 regulation

Lapachone is a natural naphthoquinone-derived compound found in Tabebuia avellanedae. It is well-known for its analgesic, anti-inflammatory, anti-microbial, diuretic, and anti-cancerous effects. However, the wound-healing effects of this compound are not known yet. The aim of this study was to investigate the wound healing activity of naphthoquinones (α-lapachone and β-lapachone) from Handroanthus impetiginosus. Expression of Sirt3, migration-related proteins (Rac1, Cdc42, α-Pak) and angiogenesis-related protein of vascular endothelial growth factor (VEGF) was monitored using western blot analysis. Blood vessel formation and tissue development were monitored by angiogenesis assay and hematoxylin & eosin (H & E) staining, respectively on mouse skin tissue samples. Both α-lapachone and β-lapachone increased Sirt3 expression in vivo, but only β-lapachone increased Sirt3 expression in vitro. Both the compounds accelerated wound healing in cultured skin cells as well as mouse skin; however, β-lapachone was more effective at lower concentrations. Both of the compounds increased the expression of migration-related proteins both in vitro and in vivo. Similarly, α-lapachone and β-lapachone increased VEGF expression, tissue development and blood vessel formation in mouse skin. These findings indicated that α-lapachone and β-lapachone are novel Sirt3 activators, and Sirt3 has a role in wound healing. Thus, Sirt3 and its regulators come out as a novel target and potential drug candidates, respectively in the important field of cutaneous wound healing.