Oleanolic acid (OA) derivatives with azaheterocyclic groups at the 2,3-positions of A ring were synthesized and their anti-proliferative effect and apoptosis induction abilities were determined in human hepatocellular carcinoma BEL-7404 cells. The results showed that compounds 4 and 5 with different azaheterocycle groups possessed better anti-proliferative activity than oleanolic acid. Meanwhile, their apoptosis induction and signal pathway were investigated which indicated that compound 4 significantly induced cell apoptosis through down-regulating Bcl-2 expression, up-regulating Bax expression, releasing cytochrome c and activating the caspase-3 pathway.
Glycyrrhetinic acid (GA) is the active compound in Glycyrrhizae radix, a famous traditional Chinese medicine. Recently the anticancer activity of GA became the focus of scientific interest and many GA derivatives were developed as anti-tumor lead compounds. We previously reported that AEGA, a GA derivative, has proliferation inhibition and apoptosis-inducing activity in various human tumor cells. The present study was undertaken to further investigate the molecular mechanisms involved in AEGA-induced apoptosis in human leukemia K562 cells. AEGA can inhibit the growth of K562 cells in dose- and time-dependent manners determined by the MTT assay. Induction of apoptosis was evidenced by morphological changes and biochemical markers such as cell shrinkage, chromatin condensation and DNA ladder formation. Further mechanistic analysis revealed that AEGA induced apoptosis through the collapse of mitochondrial membrane potential, the accumulation of the cytosolic cytochrome c and the activation of caspase-9 and caspase-3. The apoptosis induction by AEGA was associated with the alteration in the ratio of Bcl-2/Bax protein expression. These results suggest that AEGA may induce apoptosis through a mitochondria-mediated pathway, and might have the therapeutic value against hematological malignancies.
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