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J. Biol. Chem., Vol. 281, Issue 28, 19762-19771, July 14, 2006

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Molecular Iodine Induces Caspase-independent Apoptosis in Human Breast Carcinoma Cells Involving the Mitochondria-mediated Pathway^*

Ashutosh Shrivastava¹, Meenakshi Tiwari, Rohit A. Sinha, Ashok Kumar, Anil K. Balapure, Virendra K. Bajpai^¶, Ramesh Sharma, Kalyan Mitra^¶, Ashwani Tandon, and Madan M. Godbole²

From the Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, National Laboratory Animal Cell Culture and ^¶Electron Microscopy Unit, Central Drug Research Institute, Lucknow 226 014, India

Molecular iodine (I₂) is known to inhibit the induction and promotion of N-methyl-n-nitrosourea-induced mammary carcinogenesis, to regress 7,12-dimethylbenz(a)anthracene-induced breast tumors in rat, and has also been shown to have beneficial effects in fibrocystic human breast disease. Cytotoxicity of iodine on cultured human breast cancer cell lines, namely MCF-7, MDA-MB-231, MDA-MB-453, ZR-75-1, and T-47D, is reported in this communication. Iodine induced apoptosis in all of the cell lines tested, except MDA-MB-231, shown by sub-G₁ peak analysis using flow cytometry. Iodine inhibited proliferation of normal human peripheral blood mononuclear cells; however, it did not induce apoptosis in these cells. The iodine-induced apoptotic mechanism was studied in MCF-7 cells. DNA fragmentation analysis confirmed internucleosomal DNA degradation. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling established that iodine induced apoptosis in a time- and dose-dependent manner in MCF-7 cells. Iodine-induced apoptosis was independent of caspases. Iodine dissipated mitochondrial membrane potential, exhibited antioxidant activity, and caused depletion in total cellular thiol content. Western blot results showed a decrease in Bcl-2 and up-regulation of Bax. Immunofluorescence studies confirmed the activation and mitochondrial membrane localization of Bax. Ectopic Bcl-2 overexpression did not rescue iodine-induced cell death. Iodine treatment induces the translocation of apoptosis-inducing factor from mitochondria to the nucleus, and treatment of N-acetyl-L-cysteine prior to iodine exposure restored basal thiol content, ROS levels, and completely inhibited nuclear translocation of apoptosis-inducing factor and subsequently cell death, indicating that thiol depletion may play an important role in iodine-induced cell death. These results demonstrate that iodine treatment activates a caspase-independent and mitochondria-mediated apoptotic pathway.

Received for publication, January 25, 2006 , and in revised form, April 18, 2006.

^* This work was supported by the Department of Science & Technology, New Delhi (Grant SR/SO/HS/17/2003 to M. M. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a research fellowship from the Council of Scientific and Industrial Research, New Delhi (9/590(36)/2002/EMR-II), and this work constitutes a part of his Ph.D. thesis.

² To whom correspondence should be addressed: Dept. of Endocrinology, Sanjay Gandhi Post Graduate Inst. of Medical Sciences, Raebareli Rd., Lucknow 226 014, India. Tel.: 91-522-2668700 (ext. 2368); Fax: 91-522-2668017; E-mail: madangodbole{at}yahoo.co.in.

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				O Arroyo-Helguera, B Anguiano, G Delgado, and C Aceves Uptake and antiproliferative effect of molecular iodine in the MCF-7 breast cancer cell line Endocr. Relat. Cancer, December 1, 2006; 13(4): 1147 - 1158. [Abstract] [Full Text] [PDF]