Inhibitory effect of garcinol against 12-O-tetradecanoylphorbol 13-acetate-induced skin inflammation and tumorigenesis in mice

Garcinol, a polyisoprenylated benzophenone derivative, is one of the major constituents isolated from the Garcinia indica fruit rind. Previous studies have reported that garcinol exhibits many biological benefits, including anti-oxidative, anti-inflammatory, and anti-tumour activities both in vitro and in vivo. However, little is known about the garcinol-mediated protection from inflammation-associated skin tumorigenesis. The aim of this study is to evaluate the inhibitory effects of garcinol against 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced mouse skin inflammation and tumour promotion. Topical pre-treatment of mouse skin with garcinol significantly reduced TPA-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Pre-treatment with garcinol on mouse skin also suppressed the TPA-induced nuclear translocation of nuclear factor-κB (NF-κB) and its subsequent DNA binding by blocking phosphorylation of inhibitor κB α (IκBα) and the p65 subunit leading to the degradation of IκBα. Moreover, garcinol markedly reduced TPA-induced activation of extracellular signal-regulated kinases (ERK), c-Jun-N-terminal kinases (JNK), p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt, which are upstream of NF-κB. Finally, topical application of garcinol significantly attenuated 7, 12-dimethylbenz[α]anthracene (DMBA)/TPA-induced mouse skin tumour promotion by reducing tumour incidence and papilloma tumour size at 18 weeks following treatment. Based on these findings, our data suggest that garcinol may serve as a potent chemopreventive agent capable of inhibiting inflammation-associated skin tumorigenesis.