Iodine and Breast Cancer

[Guest guest]

When I asked my questions in the Curezone Forum with last night, I wasn't sure I made it absolutely clear that I was referring to breast cancer. So before I went to sleep, I sent a private message clarifying the issue. Here is the response I received. I hope this answers everyone's questions.Just wanted to stress the importance of

I2 intake for those that are dealing with FBD, PCOS, any

hormonally-driven cystic/pre-cancerous or cancerous condition. I2 is

utilized by the body in a different way that KI is, it's uptake is

different, and it performs different functions. I could attempt to

paraphrase here for you, but I won't. Lots of links for you to peruse,

I don't pretend to understand all of the technical jargon. Read and

learn.

 

The most bang for your buck, re: I2, is Lugol's solution.

 

 

http://www.thyroidscience.com/cases/Derry.Iodine.Regen.6.7.08.pdf

 

 

Lugol's Solution

 

Lugol's solution is made of 5% free Iodine and

10% potassium Iodide in water. Free iodine (elemental

iodine) is only slightly soluble in water, but 200

years ago Henri Lugol, a Paris physician, discovered

that Potassium Iodide increased free iodine's solubility

in water. Three chemical iodine species exist in

Lugol's solutions: free elemental iodine, triiodide,

and iodide. [11][12][13] Free iodine reacts with water to

make Lugol's solution brown, triiodide's weaker yellow

color is not visible, and iodide is colorless.

 

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http://www.biomedexperts.com/Abstract.bme/15922087/Inhibition_of_N-methyl-N-nitrosourea-induced_mammary_carcinogenesis_by_molecular_iodine_I2_but_not_by_iodide_I-_trea

 

 

Inhibition of N-methyl-N-nitrosourea-induced mammary carcinogenesis by

molecular iodine (I2) but not by iodide (I-) treatment Evidence that I2

prevents cancer promotion

 

We analyzed the effect of molecular iodine (I2), potassium iodide (KI)

and a subclinical concentration of thyroxine (T4) on the induction and

promotion of mammary cancer induced by N-methyl-N-nitrosourea. Virgin

Sprague-Dawley rats received short or continuous treatment. Continuous

I2 treated rats exhibited a strong and persistent reduction in mammary

cancer incidence (30%) compared to controls (72.7%). Interruption of

short or long term treatments resulted in a higher incidence in mammary

cancer compared to the control groups. The protective effect of I2 was

correlated with the highest expression of the I-/Cl- transporter

pendrin and with the lowest levels of lipoperoxidation expression in

mammary glands. Triiodothyronine serum levels and Na+/I- symporter,

lactoperoxidase, or p53 expression did not show any changes. In

conclusion continuous I2 treatment has a potent antineoplastic effect

on the progression of mammary cancer and its effect may be related to a

decrease in the oxidative cell environment.

 

 

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http://www.medsci.org/v05p0189.htm

 

 

Iodine Alters Gene Expression in the MCF7 Breast Cancer Cell Line: Evidence for an Anti-Estrogen Effect of Iodine

 

The high rate of breast disease in women with thyroid abnormalities

(both dietary and clinical) suggests a correlation between thyroid and

breast physiology [1-3]. In addition, women with breast cancer have

larger thyroid volumes then controls [2]. Multiple studies suggest that

abnormalities in iodine metabolism are the likely link [4-7].

Additionally, the impact of iodine therapy for the maintenance of

healthy breast tissue has been reported in both animal [4-7] and

clinical studies [8, 9] yet the mechanisms responsible remain unclear.

 

Iodide (I-) uptake is observed in approximately 80% of breast cancers

as well as fibrocystic breast disease and lactating breasts; however,

quantitatively, no significant iodide uptake is reported in normal,

non-lactating breast tissue [10]. Clinical trials have demonstrated

that women with cyclic mastalgia [9] or fibrocystic disease [8] can

have symptomatic relief from treatment with molecular iodine (I2).

Iodine deficiency, either dietary or pharmacologic, can lead to breast

atypia and increased incidence of malignancy in animal models [11].

Furthermore, iodine treatment can reverse dysplasia which results from

iodine deficiency [5]. Rat models using N-methyl-N-nitrosourea (NMU)

and dimethyl-benz[a]anthracene (DMBA) to induce dysplasia and

eventually carcinogenesis have shown that the presence of molecular

iodine in the animal's diet can prevent tumor formation; yet, when

iodine is removed from the diet, these animals develop tumors at rates

comparable to those of control animals [5, 7]. These data suggest that

iodine diminishes early cancer progression through an inhibitory effect

on cancer initiating cells.

 

Evidence indicates that the impact of iodine treatment on breast tissue

is independent of thyroid function. For example, iodine deficient rats

given the thyroid hormone thyroxine (T4) did not achieve reduced tumor

growth following NMU treatment suggesting that the effect of iodine on

tumor growth is independent of the thyroid gland or thyroid hormone

[7]. Additionally, Eskin et al and others have reported that

administration of molecular iodine has a greater impact on tumor growth

than the equivalent dose of iodide [5-9]. Since the thyroid primarily

utilizes iodide as opposed to iodine [5], this data supports the

hypothesis that iodine is not acting through the thyroid.

 

In addition to differences in the metabolism of iodine, the mechanisms

of iodine and iodide uptake appear to differ. While iodide uptake is

essentially via the Sodium-Iodide Symporter (NIS) in the thyroid, data

suggests that iodine uptake in the breast may be NIS-independent,

possibly through a facilitated diffusion system [12]. Together this

data indicates that the effect of iodine on breast cancer progression

is in part independent of thyroid function and suggests that iodine's

protective effect on breast cancer progression is elicited through its

direct interactions with breast cancer cells.

 

One proposed mechanism by which iodine may influence breast physiology

and cancer progression is through an interaction with estrogen

pathways. Qualitative changes in the estrogen receptor have been found

in the breasts of iodine deficient rats compared to normal euthyroid

animals suggesting that the iodine pathway may augment the synthesis of

the estrogen receptor α (ERα) [13]. Furthermore, when

estrogen-responsive and estrogen-independent tumors were transplanted

into mice, estrogen-responsive tumors had higher radioactive iodine

uptakes than estrogen-independent transplants [14]. Additionally,

iodine deficiency induced atypia is worsened by estrogen addition [15].

Together, this data supports the hypothesis that an interaction exists

between iodine and estrogen within the breast [16]. However, the

precise molecular mechanisms responsible for this interaction remain

unknown. We hypothesize that iodine effects breast physiology though an

interaction with the estrogen pathway.

 

To test our hypothesis, we analyzed the effects of Lugol's iodine

solution (5% I2, 10% KI) on global gene expression in the estrogen

responsive MCF-7 breast cancer cell line. Analysis of the gene

expression profile was used to evaluate potential mechanisms of action

of iodine.

 

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http://journal.shouxi.net/html/qikan/jcyxyswyxgc/swwlxzz/200672817/wzjh/20080828185307572_414183.html

 

 

Iodine is essential to maintaining the normalcy of the thyroid and the

breast. An iodine-deficient state renders the rat thyroid and the

breast susceptible to physiological changes and leads to atypia,

dysplasia, and hyperplasia (1). The results of iodine replacement

therapy in the iodine-deficient rat model shows that different forms of

iodine have different tissue responses; iodide (I-) is found to restore

the normal morphology and physiology of the thyroid gland, whereas

molecular iodine (I2) results in a decrease of rat breast hyperplasia

and perilobular/ductal fibrosis (2). The beneficial effect of molecular

iodine has also been documented in the human fibrocystic breast

condition and in cyclic mastalgia (3, 4). Iodine, in conjunction with

medroxy progesterone acetate (5), and an iodine-rich seaweed "wakame"

diet (6) are shown to regress 7,12-dimethylbenz(a)anthracene-induced

rat breast tumors, and this effect has been corroborated by high tumor

tissue iodine content (5, 6) and induction of apoptosis at the tumor

site (6). Iodide excess is known to induce apoptosis in the thyroid

cells in vitro (7) and also in sodium iodide symporter and

thyroperoxidase stably transfected non-small cell lung carcinoma cells

(8). Earlier studies show that sodium iodide symporter facilitates

iodide transport, and thyroperoxidase oxidizes iodide (I-) to iodine

(I2), which is important for its organification (9). Propyl-thiouracil,

an inhibitor of peroxidase, completely abolishes the cell

death-inducing effect of iodide in thyroid cells, establishing I2 as

the mediator of apoptosis (7). The enhanced expression of sodium iodide

symporter in human breast cancer tissue has been reported; however, its

significance is unknown (9, 10). In addition to this, non-lactating

breast tissue is known to be peroxidase-poor (11) and does not provide

milieu conducive for iodide organification. On the other hand,

molecular iodine is a highly reactive species and can be utilized

without involvement of sodium iodide symporter and peroxidase activity

(12).

 

Studies performed in the cell-free system show that iodine exposure to

mitochondria isolated from breast tumor tissue causes swelling,

organification of the mitochondrial proteins, and release of

apoptogenic effectors from mitochondria that cause nuclear

fragmentation (13). The mechanism of iodine action in breast cancer

cells has not been studied to date. This led us to investigate the

anti-proliferative and cytotoxic effects of iodine on breast cancer

cells, which can be mediated through apoptosis.

 

Apoptosis is a physiological cell suicide program critical to

development and tissue homeostasis. The caspases, a family of

intracellular cysteine proteases, are the central executioners of

apoptosis. Effector caspases, such as caspase-3 and -7, are activated

by initiator caspases, such as caspase-9, through proteolytic cleavage.

Once activated, effector caspases are responsible for the digestion of

a diverse array of structural and regulatory proteins, resulting in an

apoptotic phenotype (14). During apoptosis, divergent cellular

stresses, such as DNA damage, heat shock, oxidative stress, withdrawal

of growth factor, etc., also converge on mitochondria. Decrease in the

mitochondrial transmembrane potential and altered cellular redox state

are the early changes in mitochondria-mediated apoptosis (15).

Mitochondrial intermembrane space contains several proteins that can

either induce apoptosis involving caspases (e.g. cytochrome c), the

secondary mitochondrial activator of caspases (Smac) and HtrA2/Omi or

execute a caspase-independent apoptotic death program through

apoptosis-inducing factor (AIF)3 and endonuclease G (16-22). The Bcl-2

family of proteins, with both anti-apoptotic as well as pro-apoptotic

members, is implicated in the regulation of mitochondria-mediated

apoptosis. Two of the anti-apoptotic members, namely Bcl-2 and Bcl-xL,

confer resistance to apoptosis induced by a number of stimuli, whereas

the other homologues Bid, Bax, Bak, and BH-3 domain-only proteins

promote apoptosis (23, 24).

 

This study elucidates the detailed mechanism of molecular

iodine-induced apoptosis in human breast cancer cells. Iodine treatment

induces changes in members of Bcl-2 family proteins and leads to the

activation and translocation of Bax to mitochondria. The release of AIF

from mitochondria executes nuclear fragmentation in a

caspase-independent manner. The results show that iodine exhibits

strong antioxidant activity, and thiol depletion seems to play an

important role in iodine-induced apoptosis.

 

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http://www.jbc.org/cgi/content/abstract/281/28/19762

 

 

Molecular Iodine Induces Caspase-independent Apoptosis in Human Breast

Carcinoma Cells Involving the Mitochondria-mediated Pathway*

Ashutosh Shrivastava{ddagger}1, Meenakshi Tiwari{ddagger}, Rohit A.

Sinha{ddagger}, Ashok Kumar{ddagger}, Anil K. Balapure§, Virendra K.

Bajpai¶, Ramesh Sharma§, Kalyan Mitra¶, Ashwani Tandon{ddagger}, and

Madan M. Godbole{ddagger}2

 

From the {ddagger}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.

 

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http://erc.endocrinology-journals.org/cgi/content/full/13/4/1147?maxtoshow= & HITS=80 & hits=80 & RESULTFORMAT=1 & andorexacttitle=and & titleabstract=iodine & andorexacttitleabs=and & fulltext=iodine & andorexactfulltext=and & searchid=1 & FIRSTINDEX=420 & sortspec=relevance & tdate=11/30/2008 & resourcetype=HWCIT

 

 

 

This study analyzes the uptake and antiproliferative effect of two

different chemical forms of iodine, iodide (I-) and molecular iodine

(I2), in MCF-7 cells, which are inducible for the Na+/I- symporter

(NIS) and positive for pendrin (PDS). The mouse fibroblast cell line

NIH3T3 was used as control. Our results show that in MCF-7 cells, I-

uptake is sustained and dependent on NIS, whereas I2 uptake is

transient with a maximal peak at 10 min and a final retention of 10% of

total uptake. In contrast, no I- was taken up by NIH3T3 cells, and

although I2 was captured with the same time pattern as in MCF-7 cells,

its uptake was significantly lower, and it was not retained within the

cell. The uptake of I2 is independent of NIS, PDS, Na+, and energy, but

it is saturable and dependent on protein synthesis, suggesting a

facilitated diffusion system. Radioiodine was incorporated into protein

and lipid fractions only with I2 treatment. The administration of

non-radiolabeled I2 and 6-iodo-5-hydroxy-8,11,14-eicosatrienoic acid

(6-iodolactone, an iodinated arachidonic acid), but not KI,

significantly inhibited proliferation of MCF-7 cells. Proliferation of

NIH3T3 cells was not inhibited by 20 µM I2. In conclusion, these

results demonstrate that I2 uptake does not depend on NIS or PDS; they

suggest that in mammary cancer cells, I2 is taken up by a facilitated

diffusion system and then covalently bound to lipids or proteins that,

in turn, inhibit proliferation.

 

All vertebrates concentrate iodide (I-) in the thyroid gland for

thyroid hormone (TH) synthesis (Carrasco 2000, Pisarev & Gartner

2000). The mechanism of I- uptake involves active and passive transport

systems present in several organs, including thyroid and mammary glands

(Carrasco 2000, Soleimani et al. 2001, Rillema & Hill 2003a, Gillan

et al. 2004). The active transport is mediated by Na+/I- symporter

(NIS), which is a transmembrane glycoprotein that transports I- against

its concentration gradient and is perchlorate (KClO4) sensitive

(Eskandari et al. 1997, Carrasco 2000). In lactating animals, NIS

actively transports I- from the maternal plasma to the alveolar

epithelial cells of the mammary gland (Tazebay et al. 2000). In the

human breast cancer cell line MCF-7, retinoic acid (RA) treatment

increases NIS mRNA, NIS protein, and iodide uptake (Kogai et al. 2000).

Pendrin (PDS) is a facilitated diffusion transporter that is sensitive

to disulfonic-2,2'-stilbene-4,4'-diisotiocianic acid (DIDS). PDS is

also involved in I-uptake and has been described in thyroid and mammary

gland as well as in immortalized cell lines such as normal rat thyroid

FRTL-5 (Royaux et al. 2000) and in several human breast cancer cell

lines (Shennan 2001, Rillema & Hill 2003b, García-Solís et al.

2005a,b).

 

With regard to I2 uptake, studies in brown algae show that I- uptake is

dependent on oxidation, i.e. the I- in seawater is oxidized to I2 or

hypoiodous acid (HIO) by exohaloperoxidases and then penetrates into

algal cells by means of a facilitated diffusion system (Küpper et al.

1998). Thyroid cancer cells transfected with the exoenzyme

thyroperoxidase (TPO) or with both NIS and TPO (NIS/TPO) incorporate

125I-into proteins, but cells transfected only with NIS do not.

Moreover, in the presence of specific inhibitors of NIS or TPO, uptake

and protein organification of 125I- is strictly dependent on TPO but

not on NIS (Wenzel et al. 2003). These studies suggest that 125I- is

oxidized by TPO but does not use NIS to enter in the cell. Recent

studies in our laboratory have shown that normal rat mammary glands and

tumors take up I2 even in presence of KClO4 or furosamide, suggesting

that I2 uptake does not depend on NIS or PDS respectively (García-Solís

et al. 2005a,b). Several studies support the idea that the biological

effect of I- is mediated by iodinated derivatives, for example, I-

supplementation of cultured thyrocytes inhibits cell proliferation and

induces apoptosis, effects shown only if TPO activity is present.

Moreover, Vitale et al.(2000) showed that if TPO activity is blocked

with 6-n-propyl-2-thiouracil (PTU), the apoptotic I- effect is

eliminated. In addition, in lung cancer cells transfected with NIS or

NIS/TPO, the apoptotic effect is induced only in NIS/TPO transfected

cells treated with I- (Zhang et al. 2003). These data indicated that I-

must be oxidized in order to have a cytotoxic effect. In thyroid, this

effect is mediated by iodinated arachidonic acid (AA) derivatives

called: 6-iodo-5-hydroxy-8,11,14-eicosatrienoic acid or 6-iodolactone

(6-IL) and/or by iodohexadecanal (Dugrillon et al. 1990, Pisarev et al.

1994, Langer et al. 2003). In mammary gland, iodine deficiency is

involved in dysplasias (Eskin et al. 1995, Aceves et al. 2005), which

are reversible with I2 but not with I- administration (Eskin et al.

1995). Recent data generated in our laboratory showed that continuous

treatment with I2, but not with I-, has a potent antineoplasic effect

on tumoral progression in N-methyl-N-nitrosourea-treated virgin rats

(García-Solís et al. 2005a,b). The lack of I- effect has been explained

by the fact that lactoperoxidase, the enzyme that oxidizes I- and

covalently binds it to the milk protein, casein, is expressed in

mammary gland only when this tissue is lactating (Strum 1978, Shah et

al. 1986). In agreement with our findings, Shrivastava et al.(2006)

reported that I2 treatment causes apoptosis in several human breast

cancer cell lines but not in normal human peripheral blood lymphocytes.

They showed the involvement of apoptosis-inducing factor (AIF) from

mitochondria, which caused nuclear fragmentation independent of

caspases. However, neither the I2-uptake mechanism nor iodolipid

formation has been investigated in mammary cells...