Timosaponin AIII inhibits gastric cancer growth by the promotion of programmed cell death via the activation of p300/acetyl-p53 and Akt/MEK/ERK signaling.

Gastric cancer (GC) is a common cancer and causes severe deaths worldwide, while the current treatment cannot meet its medical needs. Timosaponin AIII (Timo AIII) is an active component isolated from Anemarrhena asphodeloides Bunge, which is a well-known Chinese Materia Medica and has multiple pharmacological activities, particularly anti-cancer activities. In this study, zebrafish and human GC cell models are utilized for the evaluation of the anti-GC activity of Timo AIII by integrating bioinformatics analysis and classical pharmacological approaches. We found that Timo AIII significantly decreased the GC growth in zebrafish. In human GC cell BGC-823, Timo AIII suppressed the cell viability, proliferation and migration in concentration- and time-dependent manners. Timo AIII blocked cell-cycle progression and promoted cell apoptosis. Moreover, Timo AIII activated programmed cell death (PCD), including apoptosis, ferroptosis, necroptosis and autophagy. The pharmacological inhibition of these processes and PI3K/Akt/MAPKs signaling by their specific inhibitors could partially abolish the anti-GC effect of Timo AIII. For the mechanistic study, the bioinformatics analysis revealed that p53 might be the central downstream effector of Timo AIII, promoting PCD. Timo AIII increased the intracellular protein levels of MEK, acetyl-p53 and p300 and the phosphorylation levels of Akt and MEK in BGC-823 cells, while it decreased the protein levels of p53 and Akt and the phosphorylation levels of ERK. In conclusion, Timo AIII presents anti-GC activity and the underlying mechanism is likely to be the activation of PCD via p300/acetyl-p53 and Akt/MEK/ERK signaling.