title: Toxicarioside A inhibits tumor growth and angiogenesis: involvement of TGF-β/endoglin signaling.
abstract: Toxicarioside A is a cardenolide isolated mainly from plants and animals. Emerging evidence demonstrate that cardenolides not only have cardiac effects but also anticancer effects. In this study, we used in vivo models to investigate the antitumor activities of toxicarioside A and the potential mechanisms behind them. Murine colorectal carcinoma (CT26) and Lewis lung carcinoma (LL/2) models were established in syngeneic BALB/c and C57BL/6 mice, respectively. We found that the optimum effective dose of toxicarioside A treatment significantly suppressed tumor growth and angiogenesis in CT and LL/2 tumor models in vivo. Northern and Western blot analysis showed significant inhibition of endoglin expression in toxicarioside A-treated human umbilical vein endothelial cells (HUVECs) in vitro and tumor tissues in vivo. Toxicarioside A treatment significantly inhibited cell proliferation, migration and invasion, but did not cause significant cell apoptosis and affected other membrane protein (such as CD31 and MHC I) expression. In addition, TGF-β expression was also significantly inhibited in CT26 and LL/2 tumor cells treated with toxicarioside A. Western blot analysis indicated that Smad1 and phosphorylated Smad1 but not Smad2/3 and phosphorylated Smad2/3 were attenuated in HUVECs treated with toxicarioside A. Smad1 and Smad2/3 signaling remained unchanged in CT26 and LL/2 tumor cells treated with toxicarioside A. Endoglin knockout by small interfering RNA against endoglin induced alternations in Smad1 and Smad2/3 signaling in HUVECs. Our results indicate that toxicarioside A suppresses tumor growth through inhibition of endoglin-related tumor angiogenesis, which involves in the endoglin/TGF-β signal pathway.
authors.affiliation: Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People's Republic of China.
authors.forename: Feng-Ying
authors.initials: FY
authors.lastname: Huang
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Mei
authors.forename: Yue-Nan
authors.initials: YN
authors.lastname: Li
authors.forename: Guang-Hong
authors.initials: GH
authors.lastname: Tan
authors.forename: Hao-Fu
authors.initials: HF
authors.lastname: Dai
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Guo
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Yong-Hao
authors.initials: YH
authors.lastname: Huang
authors.forename: Huan-Ge
authors.initials: HG
authors.lastname: Zhao
authors.forename: Song-Lin
authors.initials: SL
authors.lastname: Zhou
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Lin
mesh_terms: D000464:Alginates / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D002301:Cardiac Glycosides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D000071063:Endoglin; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D008956:Models, Chemical; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000464:Alginates; D002301:Cardiac Glycosides; D000071063:Endoglin; C502004:Eng protein, mouse; D006603:Hexuronic Acids; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; C575489:toxicarioside A; D020723:Glucuronic Acid