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 microM) 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 microM) 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.
Arroyo-Helguera
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Instituto de Neurobiología, Boulevard Juriquilla 3001, Juriquilla, Querétaro 76230 Instituto de Investigaciones Biomédicas, Ciudad Universitaria, Universidad Nacional Autónoma de México, D F 04510, México.
Rojas
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Delgado
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Aceves
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D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D016718:Arachidonic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001940:Breast / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007455:Iodine / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D051033:Apoptosis Inducing Factor; D016718:Arachidonic Acid; D007455:Iodine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases