Toxicarioside A inhibits tumor growth and angiogenesis: involvement of TGF-β/endoglin signaling

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 mech...

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Published in:PloS one 2012-11, Vol.7 (11), p.e50351
Main Authors: Huang, Feng-Ying, Mei, Wen-Li, Li, Yue-Nan, Tan, Guang-Hong, Dai, Hao-Fu, Guo, Jun-Li, Wang, Hua, Huang, Yong-Hao, Zhao, Huan-Ge, Zhou, Song-Lin, Lin, Ying-Ying
Format: Article
Language:English
Subjects:
Alginates - chemistry
Alternations
Angiogenesis
Animal models
Animal tissues
Animals
Anticancer properties
Apoptosis
Biology
Biotechnology
Bone marrow
Cardiac Glycosides - pharmacology
Cell growth
Cell Line, Tumor
Cell migration
Cell Movement
Cell Proliferation
Chemistry
Colorectal carcinoma
Cytotoxicity
Dose-Response Relationship, Drug
Drug dosages
Drug Screening Assays, Antitumor
Endoglin
Endothelial cells
Endothelial Cells - cytology
Female
Glucuronic Acid - chemistry
Growth factors
Heart diseases
Hexuronic Acids - chemistry
Immunotherapy
In vivo methods and tests
Inhibition
Intracellular Signaling Peptides and Proteins - metabolism
Kinases
Laboratories
Lung carcinoma
Major histocompatibility complex
Medicine
Melanoma
Membrane proteins
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Microcirculation
Models, Chemical
Neoplasm Invasiveness
Neoplasm Transplantation
Neoplasms - pathology
Neovascularization, Pathologic
Phosphorylation
Proteins
Ribonucleic acid
RNA
RNA, Small Interfering - metabolism
Signal Transduction
Signaling
siRNA
Skin cancer
Smad2 protein
Studies
Transforming Growth Factor beta - metabolism
Tumor cells
Tumors
Umbilical vein
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0050351