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 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.