The wound-healing effect of 7,3′,4′-trimethoxyflavone through increased levels of prostaglandin E2 by 15-hydroxyprostaglandin dehydrogenase inhibition

Objective To find an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) that rapidly metabolises Prostaglandin E 2 (PGE 2 ) as a mediator of wound healing, we examined seven flavonoids for this role. Results 7,3′,4′-Trimethoxyflavone (TMF) had the lowest IC 50 value of 0.34 µM for 15-PGDH inhibition but >400 µM for cytotoxicity, indicating a high therapeutic index. TMF elevated PGE 2 levels in a concentration-dependent manner in both A549 lung cancer and HaCaT cells. It also significantly increased mRNA expression of multidrug resistance-associated protein 4 (MRP4) and of prostaglandin transporter (PGT) slightly in HaCaT cells. In addition, TMF facilitated in vitro wound healing in a HaCaT scratch model, which was completely inhibited by adding both 15-PGDH and NAD + as cofactor, confirming the involvement of PGE 2 in its wound healing effect. Conclusion TMF with a high therapeutic index can facilitate wound healing through PGE 2 elevation by 15-PGDH inhibition.