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
| Autor: | Pierre Brissot, Harry S. Nick, K. Chantrel-Groussard, Gérard Lescoat, François Gaboriau, N. Pasdeloup |
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| Rok vydání: | 2007 |
| Předmět: |
DNA Replication
Carcinoma Hepatocellular Cell Survival Pyridones Apoptosis Biology Iron Chelating Agents Benzoates Ornithine decarboxylase chemistry.chemical_compound Liver Neoplasms Experimental Cell Line Tumor medicine Polyamines Animals Humans Deferiprone Viability assay Cell Proliferation DNA Primers Base Sequence Cell growth Deferasirox Cell Cycle Liver Neoplasms Cell Biology General Medicine Original Articles Triazoles Molecular biology Rats chemistry Cell culture Chemotherapy Adjuvant Polyamine Intracellular medicine.drug |
| Zdroj: | Cell proliferation. 40(5) |
| ISSN: | 0960-7722 |
| Popis: | 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. Material and 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. |
| Databáze: | OpenAIRE |
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