Iron (Fe) is essential for the proliferation of
cancer cells. A subgroup of the orthosubstituted phenolate class of Fe
chelators,
desferrithiocin [2-(3'-hydroxypyrid-2'-yl)4-methyl-delta2-thiazoline-4(S)-
carboxylic acid; DFT] and its analogues, have potential application in short-term
chemotherapy for
cancer by Fe deprivation. Their effects on cell proliferation, cell cycle progression, Fe uptake and toxicity were therefore examined in adult and fetal rat and human
hepatocellular carcinoma (HCC) cell lines, as well as in normal cells. DFT was more active than
desferrioxamine, in clinical trials as an
antineoplastic agent, consistently inhibiting cell proliferation in all cell lines (IC50 = 40 microM). 2-(2'-hydroxyphenyl-2'-yl)-delta2-thiazoline-4(S)-carboxylic
acid was the most active analogue (IC50 = 55-90 microM). Inhibition was affected by
chelator concentration and ability to prevent Fe uptake. The fetal-cell-derived HCC was more susceptible than adult HCC. Structure-activity studies revealed that thiazol methyl deletion greatly diminished antiproliferative activity of the
chelators but stereochemical orientation of COOH around C4 had no effect. Removal of the N from the
pyridine ring restored antiproliferative activity.
Chelators inhibited
DNA synthesis in the S phase. The
chelators at their IC50 concentration had little or no effect on Fe uptake in normal cells. This apparent selectivity of these
chelators for
cancer cells, coupled with their high activity, suggests that further investigation is warranted.