1SIGNALLING 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 I2 and the arachidonic acid (AA) derivative 6-iodolactone (6-IL) in both thyroid and mammary gland. 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 I2 (10-20 µM) 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 I2 (40 µM) induced apoptosis, and this effect was mediated by poly (ADP-ribose) polymerase-1 (PARP-1) and the apoptosis-induced factor (AIF), suggesting an oxidative influence of iodine at high concentrations. Our data indicate that both I2 and 6-IL trigger the same intracellular pathways and suggest that the antineoplasic effect of I2 in mammary cancer involves the intracellular formation of 6-IL. Mammary cancer cells are known to contain high concentrations of arachidonic acid, which might explain why I2 exerts apoptotic effects at lower concentrations only in tumoral cells. Page 2 of 23 3Introduction Several studies have shown the beneficial potential of molecular iodine (I2) in mammar