Source： BiofactorsDate： 2017-04-20
Deoxyelephantopin (DET), a naturally occurring sesquiterpene lactone present in Chinese medicinal herb, Elephantopus scaber has been shown to exert anti-inflammatory as well as anticancer effects in various cancer cells of human origin in vitro. However, the exact molecular mechanism underlying DET-induced apoptosis remains largely unexplored, particularly in human hepatocellular carcinoma G2 (HepG2) cells. In the present study, we found that DET inhibits proliferation and induces apoptosis in HepG2 cells in a dose-dependent manner. This DET-mediated apoptosis was found to be associated with reactive oxygen species generation, glutathione depletion and decreased activity of thioredoxin reductase, mitochondrial membrane potential disruption, Bcl-2 family proteins modulation, cytochrome c release, caspases-3 activation, PARP cleavage and inhibition of NF-κB activation. DET inhibited the constitutive as well as induced-translocation of NF-κB into nucleus and augmented the apoptotic effect of Gemcitabine. IKK-16 (NF-κB inhibitor) further enhanced the cytotoxicity of DET and gemcitabine indicating that DET induces apoptosis in HepG2 cells at least partially through inhibition of NF-κB activation. Further mechanistic study demonstrated that DET inhibits the translocation of constitutive as well as induced NF-κB into nucleus by decreasing phosphorylation of IκBα. Moreover, pretreatment of cells with 3 mm NAC reversed DET-mediated cell death and NF-κB inhibition, indicating that DET exerts its anticancer effects mainly through oxidative stress. Therefore, DET may be developed into a lead chemotherapeutic drug as a single agent or in combination with clinical drugs for the effective treatment of liver cancer.
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