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Amiodarone Induces Cytochrome c Release and Apoptosis through an Iodine-Independent Mechanism¹

Dipartimento di Biologia e Patologia Cellulare e Molecolare (M.V., T.D., G.R.) and Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica (F.D., GF.F.), Università Federico II, Naples 80131; and Centro di Endocrinologia ed Oncologia Sperimentale G. Salvatore, Consiglio Nazionale delle Ricerche (G.R.), and Dipartimento di Endocrinologia, Università di Pisa (E.M., F.B.), Pisa 56100, Italy

Address all correspondence and requests for reprints to: Dr. Mario Vitale, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Via S. Pansini 5, Naples 80131, Italy. E-mail: mavitale{at}unina.it

Amiodarone (AMD) is one of the most effective antiarrhythmic drugs available. However, its use is often limited by side-effects, mainly hypo- or hyperthyroidism. As AMD displays direct toxic effect on different cell types, we investigated the cytotoxic effect of AMD and its main metabolite, desethylamiodarone (DEA), in thyroid (TAD-2) and nonthyroid (HeLa) cell lines. Both AMD and DEA displayed a dose-dependent toxicity in TAD-2 and HeLa cells, although DEA was more effective. Both TAD-2 and HeLa cells underwent apoptosis, as evidenced by plasma membrane phosphatidylserine exposure and DNA fragmentation. Inhibition of protein synthesis with cycloheximide and inhibition of endogenous peroxidase activity with propylthiouracil did not affect this AMD- and DEA-induced apoptosis in TAD-2 cells. Western blot analysis did not display variations in the expression of p53, Bcl-2, Bcl-XL, and Bax proteins during the treatment with AMD and DEA. Generation of reactive oxygen species, investigated by flow cytometry with dichlorofluorescein diacetate, did not show the production of free radicals during drug treatment. Furthermore, Western blot analysis of cytosolic and mitochondrial fractions prepared from AMD-treated cells demonstrated that AMD induces the release of cytochrome c into the cytosol from the mitochondria.

These data indicate that AMD induces cytochrome c release from mitochondria, triggering apoptosis through an iodine-independent mechanism, and that this process is not mediated by modulation of p53, Bcl-2, Bcl-XL, or Bax protein expression and does not involve the generation of free radicals.

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