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

Abstract

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 iodineinduced cell death. These results demonstrate that iodine treatment activates a caspase-independent and mitochondria-mediated apoptotic pathway.

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

“…These authors also showed that a caspase inhibitor did not block the apoptotic effect of I 2 , suggesting that caspase pathways were not involved (Shrivastava et al 2006). In the present work, we confirmed the increase in BAX and the nuclear translocation of AIF, but we also detected the activated caspase-7 subunit of 17 kDa, as well as PARP1 cleavage, indicating the possibility that more than one pathway was activated by I 2 .…”

“…Previous studies have established that at higher concentrations, I 2 can act as a potent free radical; I 2 treatment also causes depletion of thiol levels (Vitale et al 2000, Joanta et al 2006, Shrivastava et al 2006. A shift in the redox state induces retinoblastoma gene (RB) dysfunction and results in a reduced release of E2F-binding factor and G1 cell cycle arrest.…”

Dihydroartemisinine Enhances Dictamnine-induced Apoptosis via a Caspase Dependent Pathway in Human Lung Adenocarcinoma A549 Cells

“…However, previous studies suggest the existence of mitochondria or/ and caspases-independent cell death in programmed cell death (PCD). For instance, it has been variously reported that apoptotic pathway was activated by stimuli in a mitochondria-dependent and -independent (MacDonald et al, 1999) or caspase-independent (Kang et al, 2004;Li et al, 2004;Shrivastava et al, 2006;Zhang et al, 2011) or both mitochondria-and caspase-independent manner (Chauhan et al, 2004;Bhalla et al, 2009). Our results showed that Dic did not induced any mitochondrial depolarization and caspase-3 inhibition did not prevent Dic-induced A549 cell death indicating that Dic induced a mitochondria-and caspase-3-independent A549 cell apoptosis (Figure 4).…”

Antineoplastic effect of iodine and iodide in dimethylbenz[a]anthracene-induced mammary tumors: association between lactoperoxidase and estrogen-adduct production

“…In the first case, more than one mechanism or iodine component may be triggered or generated by the iodine/iodide supplement. Several groups have postulated that the antineoplastic I 2 effect could be mediated by direct antioxidant/oxidant action at the mitochondrial level or by the formation of iodolipid intermediates such as 6-IL or iodohexadecanal (Dugrillon et al 1994, Shrivastava et al 2006, Rosner et al 2010. Our group has demonstrated that 6-IL formation in solid tumors (MNU) or cancerous cells (MCF-7) is associated with elevated concentrations of its precursor AA, and that 6-IL formation is independent of peroxidases when the supplement is I 2 (Arroyo- Helguera et al 2006).…”

“…Moreover, using lung cancer cells (without natural iodine uptake) transfected with the iodide/sodium symporter (NIS) or NIS/TPO, Zhang et al (2003) observed that only in NIS/TPO-transfected cells did excess KI induce apoptosis, indicating that I K from KI needs to be oxidized to have a cytotoxic effect. Data obtained in either in vivo (N-methylnitrosourea (MNU)) or in vitro (the human mammary cancer cell line MCF-7) models of mammary cancer show that I 2 but not I K (KI or NaI) exert an antineoplastic effect by increasing the expression of peroxisome proliferator-activated receptor g (PPARg), which triggers apoptotic mechanisms that include the Bax-caspase and apoptosis-inducing-factor (AIF) pathways (García-Solís et al 2005, Shrivastava et al 2006. Moreover, we recently demonstrated that 6-iodolactone (6-IL), which is generated by the iodination of arachidonic acid (AA), is a specific ligand of PPARg (Nuñez-Anita et al 2009).…”