title: Amurensin G, a novel SIRT1 inhibitor, sensitizes TRAIL-resistant human leukemic K562 cells to TRAIL-induced apoptosis.
abstract: Many types of cancer cells remain resistant towards TRAIL-induced cytotoxicity by the blockade of apoptotic signaling cascades. Thus, sensitizers are needed to enhance the effect of TRAIL-based cancer therapies. Although synergistic tumor cell death has been reported when various HDAC inhibitors were administered with TRAIL in a variety of human cancers, the effect of inhibitors of Class III HDAC such as SIRT1 have not been reported. We reported here for the first time that inhibition of SIRT1 augmented the cytotoxic and apoptotic effects of TRAIL on human leukemic K562 cells. Knockdown of SIRT1 or treatment with amurensin G, a potent new SIRT1 inhibitor, up-regulated the levels of DR5 and c-Myc and down-regulated the level of c-FLIP(L/S). Furthermore, knockdown of SIRT1 or treatment with amurensin G augmented the molecular responses to TRAIL, including activation of caspase-8, -9 and -3, PARP cleavage, up-regulation of Bax, and down-regulation of Bcl-2. Amurensin G-enhanced TRAIL-induced apoptosis was abrogated by caspase inhibitor Z-VAD-FMK. These findings suggest that the suppression of SIRT1 with siRNA or amurensin G sensitize the TRAIL-resistant K562 cell to TRAIL-induced apoptosis, possibly by the up-regulation of c-Myc and DR5 surface expression and the down-regulations of c-FLIP and Mcl-1. In addition, amurensin G, a potent new SIRT1 inhibitor, would be used as a sensitizer of TRAIL in TRAIL-resistant leukemic cells.
authors.affiliation: Department of Biochemistry and Medical Research Institute, Pusan National University School of Medicine, Yangsan 626-870, South Korea.
authors.forename: Hak-Bong
authors.initials: HB
authors.lastname: Kim
authors.forename: Mi-Ju
authors.initials: MJ
authors.lastname: Kim
authors.forename: Su-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Bae
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Trong Tuan
authors.initials: TT
authors.lastname: Dao
authors.forename: Won Keun
authors.initials: WK
authors.lastname: Oh
authors.forename: Chi-Dug
authors.initials: CD
authors.lastname: Kang
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D012118:Resorcinols / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000633:toxicity*
chemical_list: D003986:Dibenzocycloheptenes; D012118:Resorcinols; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C553921:amurensin G; C447939:SIRT1 protein, human; D056564:Sirtuin 1