title: Stichoposide C induces apoptosis through the generation of ceramide in leukemia and colorectal cancer cells and shows in vivo antitumor activity.
abstract: OBJECTIVE
  Marine triterpene glycosides that are physiologically active natural compounds isolated from sea cucumbers (holothurians) and sponges have antifungal, cytotoxic, and antitumor activities, whose specific molecular mechanisms remain to be elucidated. In this study, we examined if and through which mechanisms stichoposide C (STC) from Thelenota anax (family Stichopodidae) induces apoptosis in leukemia and colorectal cancer cells.
  
  
  METHODS
  We examined STC-induced apoptosis in human leukemia and colorectal cancer cells in the context of mitochondrial injury and signaling pathway disturbances, and investigated the antitumor effect of STC in mouse CT-26 subcutaneous tumor and HL-60 leukemia xenograft models.
  
  
  RESULTS
  We found that STC induces apoptosis in these cells in a dose-dependent manner and leads to the activation of Fas and caspase-8, cleavage of Bid, mitochondrial damage, and activation of caspase-3. STC activates acid sphingomyelinase (SMase) and neutral SMase, which resulted in the generation of ceramide. Specific inhibition of acid SMase or neutral SMase and siRNA knockdown experiments partially blocked STC-induced apoptosis. Moreover, STC markedly reduced tumor growth of HL-60 xenograft and CT-26 subcutaneous tumors and increased ceramide generation in vivo.
  
  
  CONCLUSIONS
  Ceramide generation by STC, through activation of acid and neutral SMase, may in part contribute to STC-induced apoptosis and antitumor activity. Thus, STC may have therapeutic relevance for human leukemia and colorectal cancer.
authors.affiliation: Department of Biochemistry, Dong-A University College of Medicine, Busan, South Korea.
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Yun
authors.forename: Eun-Seon
authors.initials: ES
authors.lastname: Park
authors.forename: Sung-Won
authors.initials: SW
authors.lastname: Shin
authors.forename: Yong-Woo
authors.initials: YW
authors.lastname: Na
authors.forename: Jin-Yeong
authors.initials: JY
authors.lastname: Han
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Jeong
authors.forename: Valeria V
authors.initials: VV
authors.lastname: Shastina
authors.forename: Valentin A
authors.initials: VA
authors.lastname: Stonik
authors.forename: Joo-In
authors.initials: JI
authors.lastname: Park
authors.forename: Jong-Young
authors.initials: JY
authors.lastname: Kwak
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism; D006027:Glycosides / Q000008:administration & dosage / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D006027:Glycosides; D017382:Reactive Oxygen Species; D014315:Triterpenes; D019014:fas Receptor; C001883:stichoposide; D013108:Sphingomyelin Phosphodiesterase; D053181:Caspase 8; D005978:Glutathione