Abstract:
Iron chelators have demonstrated significant anticancer effects in vitro, in animal studies, and in clinical trials of cancer patients. In this study, we investigated the potential utility of four iron chelators, desferrioxamine (DFO), deferiprone (L1), 311, and triapine (3AP), in the treatment of retinoblastoma.
Antiproliferative effects of the iron chelators were evaluated in two established human retinoblastoma cells lines, Y79 and Weri–RB1. Cells were treated with a range of concentrations, and antiproliferative effects were determined at 96 hours post–treatment by WST–1 Cell Proliferation Assay. Cell viability results were expressed as a percentage of vehicle–treated control values, and the concentration required to induce 50% growth inhibition (IC50) was determined. Apoptosis induction by the iron chelators was also assessed in Y79 cells. Y79 cells were treated at each agent's IC50 for 24, 48, 72, and 96 hours, and apoptotic effects were evaluated by detection of caspase 3/7 activity and by cellular morphology analysis with Hoechst 33258 staining. Caspase assay results were expressed as fold–induction of caspase activity relative to vehicle–treated control values. Hoechst assay results were expressed as fold–increase in the frequency of apoptotic cell bodies relative to vehicle–treated control values. All experiments were performed in triplicate.
All of the iron chelators demonstrated dose–dependent antiproliferative effects in both cell lines tested, with 3AP being the most and L1 being the least effective. All of the iron chelators also induced apoptosis in Y79 cells. 3AP was the most and L1 the least effective at inducing apoptosis. Results of all experiments are summarized in Table 1.
Iron chelators induce dose–dependent antiproliferative and apoptotic effects in retinoblastoma cell lines. 3AP was the most effective agent tested, inducing potent cytotoxic effects at low micromolar concentrations. Given its potency and low toxicity profile, 3AP could have clinical utility in the management of retinoblastoma.
Keywords: oncology • retinoblastoma • apoptosis/cell death