An ethyl acetate fraction ofArtemisia capillaris(ACE-63) induced apoptosis and anti-angiogenesis via inhibition of PI3K/AKT signaling in hepatocellular carcinoma

In cancer treatment, herbal medicines may be a good choice because of the reduced risk of adverse side effects. Artemisia capillaris has been recognized as a promising candidate due to its hepatoprotective effects. Herein, we investigated whether A . capillaris ‐derived fraction (ACE‐63) could inhibit the progression of hepatocellular carcinoma (HCC) and its underlying mechanism. In this study, ACE‐63 effectively inhibited the growth and proliferation of HCC cells. ACE‐63 induced apoptosis, as observed using Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, which was accompanied with increases in cleaved Poly (ADP‐ribose) polymerase (PARP) and caspase‐3 in HCC cells. Additionally, the pro‐apoptotic effect of ACE‐63 was demonstrated by a decrease in the expression of the X‐linked inhibitor of apoptosis protein (XIAP) and survivin via a loss of mitochondrial membrane potential. In an ex vivo model, ACE‐63 significantly inhibited tumor cell growth and induced apoptosis by increasing the expression of cleaved caspase‐3 and DNA fragmentation. In addition, ACE‐63 decreased the expression of hypoxia‐inducible factor‐1α and vascular endothelial growth factor and inhibited tube formation of human umbilical vein endothelial cells. A mechanistic study revealed that ACE‐63 effectively suppressed the PI3K/AKT/mTOR signaling pathways, which were observed as a target signaling by phosphokinase array. Taken together, our findings demonstrate that ACE‐63 could not only efficiently induce apoptosis but also inhibit the growth/angiogenesis of human HCC cells by blocking the PI3K/AKT/mTOR signaling pathway, suggesting that ACE‐63 may be a new chemotherapeutic candidate against HCC.