Aescin, a natural mixture of
triterpene saponins, has been reported to exert anticancer effect. Recent studies show that
aescin increases intracellular
reactive oxygen species (ROS) levels. However, whether the increased ROS play a role in the anticancer action of
aescin remains to be explored. In this study, we demonstrated that
aescin (20-80 μg/mL) dose-dependently induced apoptosis and activated
mammalian target of rapamycin (mTOR)-independent autophagy in human
hepatocellular carcinoma HepG2 cells and colon
carcinoma HCT 116 cells. The activation of autophagy favored
cancer cell survival in response to
aescin, as suppression of autophagy with ATG5 siRNAs or
3-methyladenine (3-MA), a selective inhibitor of autophagy, promoted
aescin-induced apoptosis in vitro, and significantly enhanced the anticancer effect of
aescin in vivo. Meanwhile,
aescin dose-dependently elevated intracellular ROS levels and activated
Ataxia-telangiectasia mutated
kinase/AMP-activated
protein kinase/UNC-51-like kinase-1 (ATM/AMPK/ULK1) pathway. The ROS and ATM/AMPK/ULK1 pathway were upstream modulators of the
aescin-induced autophagy, as
N-acetyl-L-cysteine (NAC) or ATM
kinase inhibitor (KU-55933) remarkably suppressed
aescin-induced autophagy and consequently promoted
aescin-induced apoptosis, whereas overexpression of ATG5 partly attenuated NAC-induced enhancement in
aescin-induced apoptosis. In conclusion, this study provides new insights into the roles of
aescin-mediated oxidative stress and autophagy in
cancer cell survival. Our results suggest that combined administration of the
antioxidants or autophagic inhibitors with
aescin might be a potential strategy to enhance the anticancer effect of
aescin.