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: Karine Chantrel-Groussard, François Gaboriau, Nicole Pasdeloup, René Havouis, Hanspeter Nick, Jean-Louis Pierre, Pierre Brissot, Gérard Lescoat
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 541 Issue 3 Pg. 129-37 (Jul 17 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16765341 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• Biogenic Polyamines
• Ethylamines
• Hydroxyquinolines
• Iron Chelating Agents
• RNA, Messenger
• Triazoles
• trensox
• Acetyltransferases
• diamine N-acetyltransferase
• Ornithine Decarboxylase
• Deferasirox

Topics

• Acetyltransferases (genetics, metabolism)
• Apoptosis (drug effects)
• Benzoates (pharmacology)
• Biogenic Polyamines (metabolism)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• DNA Replication (drug effects)
• Deferasirox
• Ethylamines (pharmacology)
• Hepatocytes (drug effects, metabolism, pathology)
• Humans
• Hydroxyquinolines (pharmacology)
• Iron Chelating Agents (pharmacology)
• Ornithine Decarboxylase (genetics, metabolism)
• RNA, Messenger (metabolism)
• Triazoles (pharmacology)