The new orally active iron chelator ICL670A exhibits a higher antiproliferative effect in human hepatocyte cultures than O-trensox.
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.
Chantrel-Groussard
Karine
K
Inserm, U522, Rennes, France.
Gaboriau
François
F
Pasdeloup
Nicole
N
Havouis
René
R
Nick
Hanspeter
H
Pierre
Jean-Louis
JL
Brissot
Pierre
P
Lescoat
Gérard
G
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
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