title: Gomisin N enhances TRAIL-induced apoptosis via reactive oxygen species-mediated             up-regulation of death receptors 4 and 5.
abstract: Pharmacological studies have revealed that lignans isolated from Schisandra chinensis, including gomisin N, show anticancer, anti-hepatotoxic, anti-oxidative and anti-inflammatory activities. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important member of the tumor necrosis factor superfamily with great potential in cancer therapy. The present study investigated whether pretreatment with gomisin N significantly enhanced TRAIL-induced cleavage of caspase-3, caspase-8 and PARP-1, which are key markers of apoptosis. Pretreatment with z-VAD-FMK, a pan-caspase inhibitor, was able to inhibit apoptosis enhanced by the combination of gomisin N and TRAIL. These results suggested that gomisin N could promote TRAIL-induced apoptosis through the caspase cascade. In search of the molecular mechanisms, we elucidated that such enhancement was achieved through transcriptional up-regulation of TRAIL receptors, death receptor 4 (DR4) and DR5. Neutralization of DR4 and DR5 could significantly reduce apoptosis induced by gomisin N and TRAIL. We also revealed that gomisin N increased the generation of reactive oxygen species (ROS). N-acetyl cysteine (NAC), an antioxidant, could inhibit ROS production and up-regulation of DR4 and DR5. Overall, our results indicated that gomisin N was able to potentiate TRAIL-induced apoptosis through ROS-mediated up-regulation of DR4 and DR5.
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine,                     University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Inoue
authors.forename: Pornthip
authors.initials: P
authors.lastname: Waiwut
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimada
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D034242:Cyclooctanes / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D011083:Polycyclic Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D034242:Cyclooctanes; D017705:Lignans; D011083:Polycyclic Compounds; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; C015499:schizandrin B