title: The new orally active iron chelator ICL670A exhibits a higher antiproliferative effect in human hepatocyte cultures than O-trensox.
abstract: By comparing the antiproliferative effect of the iron chelators ICL670A and O-trensox in the human hepatoma cell line HUH7 and human hepatocyte cultures, we have shown that ICL670A decreased cell viability, inhibited DNA replication and induced DNA fragmentation more efficiently than O-trensox. O-trensox and ICL670A induced a cell cycle blockade in G0-G1 and S phases respectively. In parallel, ICL670A inhibited polyamine biosynthesis by decreasing ornithine decarboxylase and spermidine/spermine N(1)-acetyltransferase activities. O-trensox increased polyamine biosynthesis and particularly putrescine level by stimulating spermidine-spermine N(1)-acetyltransferase activity which could activate the polyamine retro-conversion pathway. Moreover, the two chelators exhibit some cytotoxic effect in the two culture models; ICL670A was more cytotoxic than O-trensox and higher concentrations of the two chelators were necessary to induce a cytotoxicity in primary cultures versus hepatoma cells. These results suggested that ICL670A has the most efficient antitumoral effect, blocks cell proliferation by a pathway different of O-trensox and may constitute a potential drug for anticancer therapy.
authors.affiliation: Inserm, U522, Rennes, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Chantrel-Groussard
authors.forename: François
authors.initials: F
authors.lastname: Gaboriau
authors.forename: Nicole
authors.initials: N
authors.lastname: Pasdeloup
authors.forename: René
authors.initials: R
authors.lastname: Havouis
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Nick
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pierre
authors.forename: Pierre
authors.initials: P
authors.lastname: Brissot
authors.forename: Gérard
authors.initials: G
authors.lastname: Lescoat
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology*; D015317:Biogenic Polyamines / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D000077588:Deferasirox; D005021:Ethylamines / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D001565:Benzoates; D015317:Biogenic Polyamines; D000077588:Deferasirox; D005021:Ethylamines; D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; D009955:Ornithine Decarboxylase; D012333:RNA, Messenger; D014230:Triazoles; D000099228:Diamine N-Acetyltransferase; C097548:trensox