title: Scabraside D Derived from Sea Cucumber Induces Apoptosis and Inhibits Metastasis via iNOS and STAT-3 Expression in Human Cholangiocarcinoma Xenografts.
abstract: Scabraside D, a sulfated triterpene glycoside, was extracted from the sea cucumber Holothuria scabra. It shows anti-proliferation in many of cancer cell lines, but the function and mechanisms of action of scabraside D in human cholangiocarcinoma (HuCCA) have not previously determined. In this study, we investigated the activity of scabraside D on HuCCA cell apoptosis, lymphangiogenesis and metastasis in a nude mouse model. Scabraside D induced signs of apoptosis, such as cell shrinkage, nuclear condensation, nuclear fragmentation and DNA fragmentation on TUNEL assays, while effectively decreasing expression of BCl-2 but increasing caspase-3 gene level expression. Immunohistochemistry revealed that scabraside D significantly reduced lymphatic vessel density (LVD). Moreover, scabraside D treatment significantly decreased VEGF-C, MMP-9 and uPA gene expression, which play important roles in the lymphangiogenesis and invasion of cancer cells in metastasis processes. Quantitative real-time PCR showed that scabraside D significantly decreased iNOS and STAT-3 gene expression. This study demonstrated that scabraside D plays a role in activation of HuCCA tumor apoptosis and inhibition of lymphangiogenesis, invasion and metastasis through decreasing BCl-2, MMP-9, uPA and VEGF-C and increasing caspase-3 expression by suppression of iNOS and STAT-3 expression. Therefore, scabraside D could be a promising candidate for cholangiocarcinoma treatment.
authors.affiliation: Preclinic and Applied Animal Science, Mahidol University, Bangkok, Thailand E-mail : kanjana.ass@mahidol.edu.
authors.forename: Kanjana
authors.initials: K
authors.lastname: Assawasuparerk
authors.forename: Thanakorn
authors.initials: T
authors.lastname: Rawangchue
authors.forename: Rassameepen
authors.initials: R
authors.lastname: Phonarknguen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006027:Glycosides / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012616:Sea Cucumbers / Q000737:chemistry*; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D006027:Glycosides; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014315:Triterpenes; C000613500:scabraside D; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse