Santamarine Inhibits NF-κB and STAT3 Activation and Induces Apoptosis in HepG2 Liver Cancer Cells via Oxidative Stress

Sesquiterpene lactones have long been used in traditional Chinese medicines to treat inflammatory diseases. Recently, sesquiterpene lactone family compounds have been recognized as potential anticancer agents. Thus, it is necessary to explore new sesquiterpene lactones and their antitumor mechanism for cancer treatments. In the present study, we have explored the potential anti-cancer activity of a novel sesquiterpene lactone compound "santamarine" (STM) in HepG2 cells. It inhibited proliferation and induced apoptosis dose-dependently with IC50 similar to 70 mu M. Induction of apoptosis was found to be linked with increased reactive oxygen species (ROS) generation, decreased activity of thioredoxin reductase (TrxR), glutathione (GSH) depletion, mitochondrial membrane potential (Delta Psi m) dissipation, Bcl-2 family proteins modulation, cytochrome c release, caspases-9, -8 and -3 activation and PARP cleavage. Further mechanistic study demonstrated that STM inhibited the constitutive and TNF-alpha-induced translocation of NF-kappa B into nucleus by decreasing phosphorylation of IkB-alpha. Moreover, STM inhibited STAT3 activation by decreasing phosphorylation at tyrosine705. NAC pretreatment reversed the effect of STM-mediated cell death, NF-kappa B inhibition and blockage of STAT3 activity, indicating the involvement of oxidative stress in STM-mediated anticancer activity. Further studies are needed to explore the exact molecular mechanism of STM-induced apoptosis to develop it into a lead for treatment of liver cancer in future.