title: Deoxyelephantopin induces apoptosis in HepG2 cells via oxidative stress, NF-κB inhibition and mitochondrial dysfunction.
abstract: 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 IкBα. 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. © 2016 BioFactors, 43(1):63-72, 2017.
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China.
authors.forename: Tahir
authors.initials: T
authors.lastname: Mehmood
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China.
authors.forename: Amara
authors.initials: A
authors.lastname: Maryam
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China.
authors.forename: He
authors.initials: H
authors.lastname: Zhang
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China.
authors.forename: Yongming
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Khan
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China.
authors.forename: Tonghui
authors.initials: T
authors.lastname: Ma
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007783:Lactones; C498143:RELA protein, human; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D051996:Transcription Factor RelA; C528427:deoxyelephantopin; D005978:Glutathione
keywords: HepG2; NF-κB; apoptosis; deoxyelephantopin; elephantopus scaber; oxidative stress