Abstract:
Deoxyelephantopin (DET),a naturally occurring sesquiterpenelactone present in Chinese medicinal herb,Elephantopusscaberhas been shown to exert anti-inflammatory as well asanticancer effects in variouscancer cells of human origininvitro. However, the exact molecular mechanism underlyingDET-induced apoptosis remains largelyunexplored, particularlyin humanhepatocellular carcinoma G2 (HepG2) cells. Inthe present study, we found that DETinhibitsproliferation andinduces apoptosis inHepG2 cells in a dose-dependent manner.This DET-mediated apoptosis was found to be associatedwith reactive oxygenspecies generation, glutathione depletionand decreased activity of thioredoxin reductase, mitochondrialmembrane potential disruption, Bcl-2 familyproteins modulation,cytochrome c release,caspases-3 activation, PARP cleavageand inhibition of NF-κB activation. DET inhibited theconstitutive as well as induced-translocationofNF-κBintonucleus and augmented theapoptotic effect of Gemcitabine.IKK-16 (NF-κBinhibitor) further enhanced the cytotoxicity ofDET and gemcitabine indicating that DET induces apoptosis inHepG2 cells at least partially through inhibition ofNF-κBactivation.Further mechanistic study demonstrated that DETinhibits the translocation of constitutive as well as inducedNF-κBinto nucleus by decreasing phosphorylation of IκBα. Moreover,pretreatment of cells with 3 mm NAC reversed DET-mediatedcell death andNF-κBinhibition, indicating that DETexerts its anticancereffects mainly through oxidative stress.Therefore, DET may be developed into a lead chemotherapeuticdrug as a single agent or in combination with clinical drugsfor the effective treatment of liver cancer.