title: DHMEQ, a novel NF-kappaB inhibitor, induces apoptosis and cell-cycle arrest in human hepatoma cells.
abstract: Several reports have indicated that nuclear factor-kappaB (NF-kappaB) is constitutively activated in a variety of cancer cells including hepatoma cells and plays a key role in their growth and survival. Dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of an antibiotic epoxyquinomicin C is a novel NF-kappaB inhibitor. In the present study, we evaluated the effect of DHMEQ on the NF-kappaB activity in human hepatoma cells, Huh-7, HepG2 and Hep3B, and the anti-tumor effect of DHMEQ on these cells in vitro and in vivo. DHMEQ inhibited the steady-state transcriptional activity of NF-kappaB in all hepatoma cells. DHMEQ blocked the constitutive DNA-binding activity and TNF-alpha-mediated nuclear translocation of NF-kappaB in Huh-7 cells. DHMEQ (5-20 microg/ml) dose-dependently reduced the viable cell number of all hepatoma cells. DHMEQ (20 microg/ml) induced apoptosis in all hepatoma cells, especially in Hep3B cells, and cell-cycle arrest in Huh-7 and HepG2 cells. These effects were accompanied by downregulation of proteins involved in anti-apoptosis (Bcl-xL, XIAP or c-IAP2) and cell-cycle progression (cyclin D1), and induction of proteins involved in pro-apoptosis (Bax) and cell-cycle retardation (p21Waf1/Cip1), although the degree of changes by DHMEQ was different in each hepatoma cell type. Moreover, intraperitoneal administration of DHMEQ (8 mg/kg) significantly repressed the growth of Huh-7 tumor subcutaneously transplanted into BALB/c nu/nu athymic mice. Our results suggest that DHMEQ could qualify as a candidate for a new chemotherapeutic agent against human hepatoma.
authors.affiliation: First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nishimura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Kojiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Shibata
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Motoyoshi
authors.forename: Mariko
authors.initials: M
authors.lastname: Fukuta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawashimo
authors.forename: Takashi
authors.initials: T
authors.lastname: Goto
authors.forename: Naota
authors.initials: N
authors.lastname: Taura
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hamasaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakao
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D003512:Cyclohexanones / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; C464444:dehydroxymethylepoxyquinomicin