Signaling pathways involved in the antiproliferative effect of molecular iodine in normal and tumoral breast cells: evidence that 6-iodolactone mediates apoptotic effects

Previous reports have documented the antiproliferative properties of I-2 and the arachidonic acid (AA) derivative 6-iodolactone (6-IL) in both thyroid and mammary glands. In this study, we characterized the cellular pathways activated by these molecules and their effects on cell cycle arrest and apoptosis in normal (MCF-12F) and cancerous (MCF-7) breast cells. Low-to-moderate concentrations of I-2 (10-20 mu M) cause G1 and G2/M phase arrest in MCF-12F and caspase-dependent apoptosis in MCF-7 cells. In normal cells, only high doses of I-2 (40 mu M) induced apoptosis, and this effect was mediated by poly (ADP-ribose) polymerase-1 (PARP1) and the apoptosis-induced factor, suggesting an oxidative influence of iodine at high concentrations. Our data indicate that both I-2 and 6-IL trigger the same intracellular pathways and suggest that the antineoplasic effect of I-2 in mammary cancer involves the intracellular formation of 6-IL. Mammary cancer cells are known to contain high concentrations of AA, which might explain why I-2 exerts apoptotic effects at lower concentrations only in tumoral cells.