(1S,2S,3E,7E,11E)-3,7,11,15-Cembratetraen-17,2-olide, a Cembrenolide Diterpene from Soft Coral Lobophytum sp., Inhibits Growth and Induces Apoptosis in Human Colon Cancer Cells through Reactive Oxygen Species Generation

• Published in: Biological & pharmaceutical bulletin Vol. 35; no. 7; pp. 1054 - 1063
• Main Authors: Hong, Ji-Young, Boo, Hye-Jin, Kang, Jung-Il, Kim, Min-Kyoung, Yoo, Eun-Sook, Hyun, Jin-Won, Koh, Young-Sang, Kim, Gi Young, Maeng, Young Hee, Hyun, Chang Lim, Chang, Weon Young, Kim, Young Ho, Kim, Young Ree, Kang, Hee-Kyoung
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 2012; Japan Science and Technology Agency
• Subjects: (1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide; Animals; Anthozoa; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; BH3 Interacting Domain Death Agonist Protein - metabolism; Caspases - metabolism; Catalase - metabolism; Cell Proliferation - drug effects; cembrenolide diterpene; Colonic Neoplasms; Diterpenes - pharmacology; Glutathione Peroxidase - metabolism; Heme Oxygenase-1 - metabolism; HT-29; HT29 Cells; Humans; Lobophytum; Poly(ADP-ribose) Polymerases - metabolism; Protein Kinases - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; reactive oxygen species; Reactive Oxygen Species - metabolism; STAT3 Transcription Factor - metabolism; Superoxide Dismutase - metabolism
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b11-00024

We observed that (1S,2S,3E,7E,11E)-3,7,11,15-Cembratetraen-17,2-olide (LS-1), marine cembrenolide diterpene, inhibited growth and induced apoptosis in colon cancer cells via a reactive oxygen species (ROS) dependent mechanism. Treatment of HT-29 cells with LS-1 resulted in ROS generation, which was accompanied by disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, sub-G1 peak accumulation, activation of Bid, caspase-3, -8, and -9, and cleavage of poly(ADP-ribose) polymerase (PARP) along with the suppressive expression of B cell lymphoma-2 (Bcl-2). All these effects were significantly blocked on pretreatment with the ROS inhibitor N-acetylcysteine (NAC), indicating the involvement of increased ROS in the proapoptotic activity of LS-1. Moreover, we showed that LS-1 induced the phosphorylation of c-Jun N-terminal kinase (JNK) and dephosphorylation of p38, extracellular signal-regulated kinase (ERK), Akt, Src and signal transducer and activator of transcription (STAT)3, which were effectively attenuated by NAC. In addition, the expressions of antioxidant catalase and glutathione peroxidase were abrogated by treatment using LS-1 with or without NAC. These findings reveal the novel anticancer efficacy of LS-1 mediated by the induction of apoptosis via ROS generation in human colon cancer cells.