Antitumor activity of jujuboside B and the underlying mechanism via induction of apoptosis and autophagy

J Nat Prod. 2014 Feb 28;77(2):370-6. doi: 10.1021/np401022g. Epub 2014 Feb 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Anthracenes
  • Macrolides
  • Saponins
  • jujuboside B
  • pyrazolanthrone
  • bafilomycin A1
  • JNK Mitogen-Activated Protein Kinases
  • Caspase 3