Antiproliferative and apoptotic effects in rat and human hepatoma cell cultures of the orally active iron chelator ICL670 compared to CP20: a possible relationship with polyamine metabolism.
OBJECTIVE
Iron loading has been observed to have a hyperproliferative effect on hepatocytes in vitro and on tumour cells in vivo; removal of this iron being required to induce antitumour activity.


METHODS
Antiproliferative effects of orally active tridentate iron chelator ICL670 (deferasirox) and bidentate iron chelator CP20 (deferiprone), mediated through the chelation of intracellular iron, were compared in rat hepatoma cell line FAO and human hepatoma cell line HUH7.


RESULTS
In FAO cell cultures, we have shown that ICL670 decreased cell viability and DNA replication and induced apoptosis more efficiently than an iron-binding equivalent concentration of CP20. Moreover, ICL670 decreased significantly the number of the cells in G(2)-M phase. In the HUH7 cell cultures, ICL670 and a four-time higher iron-binding equivalent concentration of CP20, decreased cell viability and DNA replication in the same range. CP20 increased the number of the cells in G(2)-M phase. However, ICL670 inhibited polyamine biosynthesis by decreasing ornithine decarboxylase mRNA level; in contrast, CP20 increased polyamine biosynthesis, particularly putrescine level, by stimulating spermidine-spermine N(1)-acetyl transferase activity that could activate the polyamine retro-conversion pathway. By mass spectrometry, we observed that ICL670 cellular uptake was six times higher than CP20.


CONCLUSIONS
These results suggest that ICL670 has a powerful antitumoural effect and blocks cell proliferation in neoplastic cells by a pathway different from that of CP20 and may constitute a potential adjuvant drug for anticancer therapy.
Lescoat
G
G
Inserm, U522, Rennes, F-35000, Rennes cedex, France. gerard.lescoat@rennes.inserm.fr
Chantrel-Groussard
K
K
Pasdeloup
N
N
Nick
H
H
Brissot
P
P
Gaboriau
F
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001565:Benzoates / Q000493:pharmacokinetics / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D017931:DNA Primers / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects; D000077588:Deferasirox; D000077543:Deferiprone; D006801:Humans; D007502:Iron Chelating Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011073:Polyamines / Q000378:metabolism; D011728:Pyridones / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
D001565:Benzoates; D017931:DNA Primers; D007502:Iron Chelating Agents; D011073:Polyamines; D011728:Pyridones; D014230:Triazoles; D000077543:Deferiprone; D000077588:Deferasirox