Desferrithiocin is a more potent antineoplastic agent than desferrioxamine

A. Kicic, Anita Chua, Erica Baker

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    Abstract

    Desferrithiocin (DFT) is an orally effective Fe chelator, with a similar high affinity and selectivity for Fe to desferrioxamine (DFO), which has been shown clinically to possess antineoplastic activity. In this study, DFT was assessed for antineoplastic potential in hepatocellular carcinoma cell lines (HCC). This was done as there are few treatments for this aggressive neoplasm. The effects of DFT on cell proliferation, cell cycle progression, Fe uptake and toxicity were examined. To establish whether DFT was selective for cancer cells a comparison was made with normal (non-proliferating) hepatocytes and non-tumorigenic (proliferating) fibroblasts (SWISS-3T3). DFT was a potent inhibitor of HCC proliferation (IC(50)similar to40 mum). DFO also inhibited HCC proliferation under the same conditions, but was much less active (IC50 = 110-210 mum). When saturated with Fe, the activity of DFT, like DFO, was greatly diminished, suggesting it may act by depriving the cells of Fe or inactivating essential Fe pool(s). Indeed DFT rapidly decreased Fe uptake from Tf-Fe-59 by hepatoma cells and also by normal hepatocytes. However, DFT (and DFO) had much less effect on cell survival in hepatocytes and fibroblasts than in hepatoma cells. DFT may, like DFO, inhibit the cell cycle in the S phase of DNA synthesis. Both chelators showed low toxicity, These results indicate that DFT has potent antineoplastic activity in HCC. Further investigation into the DFT class of Fe chelators seems warranted, particularly in view of its high activity in relation to DFO, a chelator which is already in clinical trial for neuroblastoma.
    Original languageEnglish
    Pages (from-to)1393-1402
    JournalBritish Journal of Pharmacology
    Volume135
    DOIs
    Publication statusPublished - 2002

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