Anacardic Acid (6-Pentadecylsalicylic Acid) Inhibits Tumor Angiogenesis by Targeting Src/FAK/Rho GTPases Signaling Pathway

Abstract

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 ϭ 10) and VEGF-triggered corneal neovascularization in vivo (n ϭ 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 ϭ 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.

Anacardic Acid Enhances the Proliferation of Human Ovarian Cancer Cells

“…As we have discussed above, AA plays a diverse role in various cancers and acts through multiple pathways. For example, the potent inhibitory activity of AA on VEGF-stimulated migration, capillary structure formation, attachment and paxillin activation in endothelial cells has previously been reported [11]. However, in our study, AA was found to promote the expression of VEGF mRNA and protein in ovarian cancer cells Therefore, we speculate that AA may promote migration and invasion in ovarian cancer via the VEGF pathway.…”

Src: Marker or Actor in Prostate Cancer Aggressiveness

“…Src and VEGF cooperation can be targeted by the Src-specific inhibitor dasatinib (50) and several other pharmacological compounds (35, 53–58). Of strong interest for clinical applications, in vivo studies have also demonstrated that Src inhibition is able to provoke decreased tumoral xenograft growth by reducing angiogenesis (50, 56). …”

Epigenetic Modifications: Therapeutic Potential in Cancer

“…Garcinol and anacardic acid are both EP300 and KAT2B HAT inhibitors. Antitumor activities of all the three molecules in a wide variety of cancers include interefernce with different cell signaling pathways, like cell cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and downregulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF-κB, TNF, IL-6, IL-1, COX-2, and 5-LOX) (Anand et al 2008;Wu et al 2011;Ahmad et al 2012). Green tea polyphenols suppresses class I histone deacetylases, and thus causes cell cycle arrest and apoptosis in prostate cancer (Thakur et al 2012).…”