title: 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 = 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.
authors.affiliation: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Rd., Shanghai 200241, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Lijun
authors.initials: L
authors.lastname: He
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Yi
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Pang
mesh_terms: D048729:Anacardic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects / Q000473:pathology; D016510:Corneal Neovascularization / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D020741:rho GTP-Binding Proteins / Q000819:agonists; D054460:rho-Associated Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D048729:Anacardic Acids; D020533:Angiogenesis Inhibitors; C088115:anacardic acid; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051417:Focal Adhesion Kinase 1; D019061:src-Family Kinases; D054460:rho-Associated Kinases; D020558:GTP Phosphohydrolases; D020741:rho GTP-Binding Proteins