Stichoposide C induces apoptosis through the generation of ceramide in leukemia and colorectal cancer cells and shows in vivo antitumor activity.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Seong-Hoon Yun, Eun-Seon Park, Sung-Won Shin, Yong-Woo Na, Jin-Yeong Han, Jin-Sook Jeong, Valeria V Shastina, Valentin A Stonik, Joo-In Park, Jong-Young Kwak
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 21 Pg. 5934-48 (Nov 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 23132899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents
• Ceramides
• Glycosides
• Reactive Oxygen Species
• Triterpenes
• fas Receptor
• stichoposide
• Sphingomyelin Phosphodiesterase
• Caspase 8
• Glutathione

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects, genetics)
• Caspase 8 (metabolism)
• Cell Line, Tumor
• Ceramides (metabolism)
• Colorectal Neoplasms (genetics, metabolism)
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Gene Knockdown Techniques
• Glutathione (metabolism)
• Glycosides (administration & dosage, pharmacology)
• HL-60 Cells
• Humans
• Leukemia (genetics, metabolism)
• Mice
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Sphingomyelin Phosphodiesterase (metabolism)
• Triterpenes (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays
• fas Receptor (genetics, metabolism)