title: Antitumor activity of jujuboside B and the underlying mechanism via induction of apoptosis and autophagy.
abstract: Jujuboside B (1) is one of the saponins isolated from the seeds of Zizyphus jujuba var. spinosa, which are used as a well-known traditional medicine for the treatment of insomnia and anxiety in East Asian countries. This is the first study to investigate the antitumor mechanism of 1 in vivo and in vitro. The results showed that 1 induced apoptosis and autophagy in AGS and HCT 116 human cancer cells and also effectively suppressed tumor growth in a nude mouse xenograft model bearing HCT 116 cells. The apoptosis-inducing effect of 1 was characterized by annexin V/propidium iodide staining, sub-G1 phase increase, and caspase-3 activation. Mechanistic studies showed that 1-induced apoptosis is associated with the extrinsic pathway through an increase in FasL and caspase-8 activation. Moreover, 1 activated p38/c-Jun N-terminal kinase (JNK), and the extrinsic pathway-mediated apoptosis was attenuated by both SB202190 (a p38 inhibitor) and SP600125 (a JNK inhibitor). The autophagy-inducing effect was indicated by the formation of cytoplasmic vacuoles and microtubule-associated protein 1 light chain-3 II (LC3-II) conversion. The autophagy inhibitor bafilomycin A1 (BaF) decreased 1-induced cell viability and increased pp38, pJNK, FasL, caspase-8 activation, and caspase-3 activation. Taken together, these results demonstrate that 1 induced protective autophagy to retard extrinsic pathway-mediated apoptosis.
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University , Seoul 151-742, Republic of Korea.
authors.forename: Mei-Ying
authors.initials: MY
authors.lastname: Xu
authors.forename: So Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Sam Sik
authors.initials: SS
authors.lastname: Kang
authors.forename: Yeong Shik
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D012503:Saponins / Q000737:chemistry / Q000494:pharmacology*; D012639:Seeds / Q000737:chemistry; D031957:Ziziphus / Q000737:chemistry*
chemical_list: D000873:Anthracenes; D018942:Macrolides; D012503:Saponins; C540008:jujuboside B; C432165:pyrazolanthrone; C040929:bafilomycin A1; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3