Pterostilbene, a natural analogue of resveratrol, potently inhibits 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin carcinogenesis

Abstract

We reported previously that pterostilbene, a natural analogue of resveratrol from blueberries, strongly suppressed lipopolysaccharide-induced up-expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in murine macrophages. In this study, we further investigated pterostilbene's molecular mechanism of action and its anti-tumor properties. Pretreatment with pterostilbene has resulted in the reduction of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced nuclear translocation of the nuclear factor-κB (NFκB) subunits. Pterostilbene also reduced TPA-induced phosphorylation of IκBα and p65 and caused subsequent degradation of IκBα. Moreover, pterostilbene markedly suppressed TPA-induced activation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK)1/2, phosphatidylinositol 3-kinase (PI3K) and Akt, which are upstream of NFκB and activator protein 1 (AP-1). Furthermore, pterostilbene significantly inhibited 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced skin tumor formation measured by the tumor multiplicity of papillomas at 20 weeks. The presented data has, for the first time, revealed that pterostilbene is an effective anti-tumor agent that functions by downregulating inflammatory iNOS and COX-2 gene expression in mouse skin. It is suggested that pterostilbene is a novel functional agent capable of preventing inflammation-associated tumorigenesis.