Anacardic acid (6-pentadecylsalicylic acid), a natural inhibitor of
histone acetyltransferase from Amphipterygium adstringens, has been shown to have anti-inflammatory, anticancer, antioxidative, and antimicrobial functions. However, whether this
salicylic acid could block angiogenesis has not been elucidated to date. Here, we postulate that
anacardic acid affects multiple steps of
tumor angiogenesis to contribute to
tumor inhibition. In this study, we found that
vascular endothelial growth factor (
VEGF)-induced cell proliferation, migration, and adhesion and capillary-like structure formation of primary cultured human umbilical vascular endothelial cells (HUVECs) could all be significantly suppressed by
anacardic acid in vitro, without detectable cellular toxicity. Furthermore,
anacardic acid effectively inhibited vascular development in chick embryo chorioallantoic membrane ex vivo (n = 10) and
VEGF-triggered
corneal neovascularization in vivo (n = 10). A mechanistic study revealed that
anacardic acid blocked activities of Src and FAK
kinases in concentration- and time-dependent manners in HUVECs, resulting in activation of RhoA-
GTPase and inactivation of Rac1- and Cdc42-GTPases. Of note, when
anacardic acid (2 mg/kg per day) was subcutaneously administrated to mice bearing human prostate
tumor xenografts (n = 6-7), the volume and weight of solid
tumors were significantly retarded. Src, Ki-67, and CD31 immunohistochemical staining further revealed that Src
protein expression,
tumor cell proliferation, and microvessel density could be remarkably suppressed by
anacardic acid. Taken together, our findings demonstrate for the first time that
anacardic acid functions as a potent
tumor angiogenesis inhibitor by targeting the Src/FAK/
Rho GTPase signaling pathway, leading to significant suppression of prostate
tumor growth.