Antitumor Activity of Jujuboside B and the Underlying Mechanism via Induction of Apoptosis and Autophagy

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 v...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2014-02, Vol.77 (2), p.370-376
Main Authors: Xu, Mei-Ying, Lee, So Young, Kang, Sam Sik, Kim, Yeong Shik
Format: Article
Language:English
Subjects:
Animals
Anthracenes - pharmacology
Apoptosis - drug effects
Autophagy - drug effects
Caspase 3 - drug effects
Caspase 3 - metabolism
Cell Survival - drug effects
HCT116 Cells
Humans
JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors
Macrolides - pharmacology
Mice
Saponins - chemistry
Saponins - pharmacology
Seeds - chemistry
Ziziphus - chemistry
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Summary: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.
ISSN:0163-3864
1520-6025
DOI:10.1021/np401022g