Novel ginsenoside derivatives induce apoptosis in HepG-2 cells via the MDM2-p53 signaling pathway

Abstract

In this study, 6-aryl-5-cyanopyrimidines and quinazolinones were introduced into panaxadiol (PD) to synthesize 25 new panaxadiol derivatives. The cytotoxicity of these compounds against three cancer cells and one normal cell was examined by methylthiazoletetrazolium (MTT) cytotoxicity experiment. The findings demonstrated that PD cyanopyrimidine derivatives have superior anti-proliferative effects over quinazoline derivatives. Among them, PM14 had the strongest inhibitory activity on the proliferation of human hepatoma cell lines (HepG-2), the IC₅₀ value was 2.13 ± 0.20 μM. 4',6-diamidino-2-phenyl-indole (DAPI) staining showed that PM14 made HepG-2 nucleus shrink and had obvious apoptosis. Mechanistic studies confirmed that the derivative PM14 activates p53 signaling pathway by reducing the expression of MDM2 protein, and further induces an increase in the intracellular Bax/Bcl-2 ratio, down-regulated the expression of Caspase-3, up-regulated Cl-Caspase-3 expression, eventually leading to cell apoptosis. This lays the foundation for subsequent development of derivatives with stronger anti-proliferative activity.

Keywords: Apoptosis; Cyanopyrimidine; MDM2/p53; Panaxadiol; Quinazoline.