Iodine Articles 5

© 2012

Uptake and antitumoral effects of iodine and 6-iodolactone in differentiated and undifferentiated human prostate cancer cell lines

            (Aranda, Sosa et al. 2012) Download

BACKGROUND: Evidence indicates that iodine per se could be implicated in the physiology of several organs that can internalize it. In thyroid and breast cancer, iodine treatments inhibit cell proliferation and induce apoptosis through a direct (mitochondria) and/or indirect effect (iodolipid generation). Here, we determined the uptake of iodide (I(-) ) and iodine (I(2) ), as well as the antiproliferative and apoptotic effects of 6-iodolactone (6-IL) and both forms of iodine in human prostate cells lines. METHODS: Non-cancerous (RWPE-1) and cancerous (LNCaP, DU-145) cells, as well as nude mice xenotransplanted with DU-145 cells were used as cancer models. Iodine uptake was analyzed with radioactive tracers, transporter expression by qRT-PCR, cell proliferation by blue trypan, apoptosis by enzyme immunoassay or fluorescence, BAX and BCL-2 by western-blot, and caspsase 3 by enzymatic assay. RESULTS: All three cell lines take up both forms of iodine. In RWPE-1 cells, I(-) uptake depends on the Na(+) /I(-) symporter (NIS), whereas it was independent of NIS in LNCaP and DU-145 cells. Antiproliferative effects of iodine and 6-IL were dose and time dependent; RWPE-1 was most sensitive to I(-) and 6-IL, whereas LNCaP was more sensitive to I(2) . In the three cell lines both forms of iodine activated the intrinsic apoptotic pathway (increasing the BAX/BCL-2 index and caspases). Iodine supplementation impaired growth of the DU-145 tumor in nude mice. CONCLUSION: Normal and cancerous prostate cells can take up iodine, and depending on the chemical form, it exerts antiproliferative and apoptotic effects both in vitro and in vivo. Prostate (c) 2012 Wiley Periodicals, Inc.


Transformation of arachidonic acid into an iodolactone by the rat thyroid

            (Boeynaems and Hubbard 1980) Download

In the presence of iodide and hydrogen peroxide, lactoperoxidase, an enzyme model for thyroid peroxidase, catalyzed the conversion of arachidonic acid into several iodinated products. The major product was identified as 6-iodo-5-hydroxy-eicosatrienoic acid, delta-lactone (iodolactone), on the basis of 125I incorporation, mass spectrometry, proton magnetic resonance spectroscopy, and chemical modifications. Using this compound as a standard, two methods were developed to establish and quantitate the production of iodolactone by the rat thyroid in vitro: 125I labeling followed by reversed phase high pressure liquid chromatography and combined gas chromatography-mass spectrometry. Addition of iodide and arachidonic acid to rat thyroid lobes resulted in the formation and release of the iodolactone, which was inhibited by methimazole. These data suggest that peroxidases capable of oxidizing halides could provide a new pathway of arachidonic acid metabolism, besides cyclooxygenase and lipoxygenases.

Effects of iodine on thyroid function in man

         (Braverman 1991) Download

Iodine Use in the Treatment and Prevention of Poliomyelitis

            (Edward 1954) Download

The role of iodine and delta-iodolactone in growth and apoptosis of malignant thyroid epithelial cells and breast cancer cells

            (Gartner, Rank et al. 2010) Download

OBJECTIVE: As we previously demonstrated, the inhibitory effect of iodine on thyroid cell growth is mediated by iodolactones, especially 6-iodo-5-hydroxy-eicosatrienoic acid (delta-iodolactone). In this communication we compare the effect of iodide, molecular iodine and delta-iodolactone on growth inhibition and apoptosis on three human thyroid carcinoma cell lines (B-CPAP cells, FTC-133 cells and 8505C cells) as well as on human breast cancer cells (MCF 7). METHODS: Thyroid carcinoma cells were cultured in Dulbecco's modified Eagle's medium (DMEM) and MCF 7 cells in Rowswell Park Memorial Institute (RPMI) culture medium, both containing 10% (v/v) Fetal Calf Serum (FCS), until they were confluent. Around 2000 cells were then distributed in 12-well plates and grown for 48 h in either DMEM (thyroid cancer cells) or in RPMI medium (MCF 7 cells) both containing 5% FCS. Thereafter, different concentrations of iodide, iodine or delta-iodolactone were added for 24 h. Growth rate was estimated by cell counting in a Coulter Counter adapted for epithelial cells. Apoptosis was determined by a mitochondrial potential assay. RESULTS: The growth rate of B-CPAP cells was unaffected by iodide, but was reduced by high concentreations of molecular iodine (100 and 500 microM). However, delta-iodolactone significantly reduced cell proliferation already with low concentrations (5 microM and 10 microM) and further in a dose-dependent manner up to 82%. FTC-133 and 8505C cells were unaffected by iodide, iodine or delta-iodolactone. In contrast, in MCF 7 cells, molecular iodine (100 microM) inhibited growth from 100% to 83% but delta-iodolactone (1, 5 and 10 microM) dose-dependently decreased growth rate from 100% to 82% and 62%, respectively. The inhibition of growth was through apoptosis, and not necrosis, as the amount of apoptotic cells corresponded to the growth inhibition. CONCLUSION: delta-Iotaodolactone seems to be the main iodocompound which can inhibit growth and induce apoptosis in B-CPAP cells as well as in MCF 7 breast cancer cells.

Influence of iodide and iodolactones on thyroid apoptosis. Evidence that apoptosis induced by iodide is mediated by iodolactones in intact porcine thyroid follicles

            (Langer, Burzler et al. 2003) Download

Iodine induced thyroid involution is caused by apoptosis rather than necrosis. This effect of iodide on apoptosis of thyroid epithelial cells may be not a direct one but mediated by iodinated derivatives i.e. of polyunsaturated fatty acids, especially of iodolactones, which have previously shown to inhibit thyroid cell proliferation. We studied the influence on apoptosis of iodide (2 microM and 20 microM) and iodolactone (0.05 microM and 0.5 microM), with and without TSH (1 mU/ml), using a well characterized ex vivo- culture system of intact porcine thyroid follicles in three-dimensional culture. Apoptosis and necrosis was evaluated by electron-microscopy. Stimulation with 2 and 20 microM iodide rapidly induced a rate of apoptosis (4 - 6 %) comparable to about 40-fold lower doses of delta-iodolactone (0.05 microM and 0.5 microM). Addition of TSH (1 mU/ml) caused a slight but not significant further increase of the incidence of apoptotic cells. The rate of necrotic thyroid epithelial cells (1 - 2 %) was similar in all experiments. As delta-iodolactone in very low concentrations--comparable to iodide in higher concentrations--not only inhibits growth but also induces apoptosis, it has to be supposed that the effect of iodide is mediated by this iodinated compound. However, further experiments are necessary to confirm this hypothesis. In addition it could be demonstrated, that apoptosis is a very rapid and limited process in intact follicles. This also may explain, why iodine supplementation even in high doses does not lead to thyroid atrophy but only normalisation of thyroid size. These results confirm that apoptosis is an important regulated and limited mechanism in goiter involution.


A complex between 6-iodolactone and the peroxisome proliferator-activated receptor type gamma may mediate the antineoplastic effect of iodine in mammary cancer

            (Nunez-Anita, Arroyo-Helguera et al. 2009) Download

Recently we and other groups have shown that molecular iodine (I(2)) exhibits potent antiproliferative and apoptotic effects in mammary cancer models. In the human breast cancer cell line MCF-7, I(2) treatment generates iodine-containing lipids similar to 6-iodo-5-hydroxy-eicosatrienoic acid and the 6-iodolactone (6-IL) derivative of arachidonic acid (AA), and it significantly decreases cellular proliferation and induces caspase-dependent apoptosis. Several studies have shown that AA is a natural ligand of the peroxisome proliferator-activated receptors (PPARs), which are nuclear transcription factors thought to participate in regulating cancer cell proliferation. Our results show that in MCF-7 cells: (1) 6-IL binds specifically and with high affinity to PPAR proteins (EMSA assays), (2) 6-IL activates both transfected (by transactivation assays) and endogenous (by lipid accumulation) peroxisome proliferator response elements, and (3) 6-IL supplementation increases PPAR gamma and decreases PPAR alpha expression. These results implicate PPARs in a molecular mechanism by which I(2), through formation of 6-IL, inhibits the growth of human breast cancer cells.

Studies on the goiter inhibiting action of iodolactones

            (Pisarev, Krawiec et al. 1994) Download

The thyroid gland synthesizes 6-delta-iodolactone, a compound shown to inhibit goiter growth in vivo and cell proliferation in culture. The present studies were performed to characterize this effect further with the aim of exploring the possible therapeutic action of iodolactones. Prevention assay: rats were treated simultaneously with a goitrogen, methylmercaptoimidazole, and either 6-delta-iodo-lactone or 14-iodo-omega-lactone, a synthetic derivative, given either i.p. or p. o. Both compounds caused a significant decrease in thyroid weight irrespective of the route of administration, but oral administration was less effective. A dose-response relationship was observed, the minimal effective dose (i.p.) being 3 micrograms/day. Involution assay: goiter was first induced with methylmercaptoimidazole and then the iodolactones were injected. Both compounds caused a significant involution, which was dose-related. Acute (10 days) administration of the iodolactones did not produce significant changes in several serum parameters (total T3 and T4, cholesterol, total protein, urea and acetylcholinesterase). These results give further support to the potential therapeutic application of iodolactones.


Antiproliferative/cytotoxic activity of molecular iodine and iodolactones in various human carcinoma cell lines. No interfering with EGF-signaling, but evidence for apoptosis

            (Rosner, Torremante et al. 2010) Download

Twelve human cancer cell lines and one non-malignant cell line were investigated with respect to a potential antiproliferative/cytotoxic activity of molecular iodine and iodolactones. Except CCL221 colon carcinoma cells, the growth of all cancer cell lines decreased if the cells were cultured in the presence of 10 microM molecular iodine (I(2)) for at least two days. delta-iodolactone (IL, 5 microM) was found to have a similar effect. SH-SY5Y neuroblastoma cells turned out to be most susceptible to both iodine compounds (total inhibition), followed by MCF-7 mammary carcinoma cells (60% and 77.7% inhibition in the presence of I(2) respect. IL) and HS24 lung carcinoma cells (36.3% respect. 40.3% inhibition). In contrast, MCF-10 normal mammary epithelial cells were much less affected by the iodine treatment. In both, SH-SY5Y and MCF-7 cells, I(2) and IL also abolished EGF-induced promotion of cell growth completely. This effect was, however, not due to an interfering with EGF-signaling, because I(2) and IL did not affect the phosphorylation of EGF-receptors, EGF-induced activation of MAP-kinase (Erk(1/2)), or EGF-induced lamellar actin protrusion. A disruption by molecular iodine of mitochondrial transmembrane electrical potential, which was prevented by a pre-treatment of the cells with N-acetyl-cysteine, supports a mitochondria-mediated apoptotic mechanism.

Potassium iodide remains the most effective therapy for cutaneous sporotrichosis

            (Sandhu and Gupta 2003) Download

Sporotrichosis is a subcutaneous fungal infection caused by the dimorphic fungus Sporothrix schenckii. Itraconazole has largely replaced older therapies, but we present a case of lymphocutaneous sporotrichosis that failed to respond to an adequate course of itraconazole yet responded dramatically to treatment with saturated solution of potassium iodide (SSKI).

Biochemical changes during goiter induction by methylmercaptoimidazol and inhibition by delta-iodolactone in rat

            (Thomasz, Oglio et al. 2010) Download

BACKGROUND: We have demonstrated that the administration of delta-iodolactone (i.e., 5-iodo-delta lactone) of arachidonic acid (IL-delta), a mediator in thyroid autoregulation, prevents goiter induction by methylmercaptoimidazol (MMI) in rats. Other studies have shown that transforming growth factor beta-1 (TGF-beta1) mimics some of the actions of excess iodide, but its participation in autoregulation is disputed. The present studies were performed to test the hypotheses that IL-delta decreases thyroid growth by inhibition of cell proliferation and/or by stimulation of apoptosis due to oxidative stress, that TGF-beta is stimulated by an excess of iodide and by IL-delta, and that c-Myc and c-Fos expression are upregulated during goiter induction and downregulated during goiter inhibition. METHODS: Rats were treated with MMI alone or together with iodide or IL-delta. Thyroid weight, cell number, cell proliferation, apoptosis, and oxidative stress were determined. Proliferating cell nuclear antigen (PCNA), TGF-beta1, TGF-beta3, c-Myc, and c-Fos were measured by Western blot. RESULTS: MMI caused a progressive increase in thyroid weight accompanied by an increase in cell number, asymmetry of the ploidy histograms, and PCNA, c-Fos, and c-Myc expression. In addition, an early increase of apoptosis was observed. Peroxides as well as glutathione peroxidase and catalase activities were also increased in goitrous animals. The inhibitory action of IL-delta on goiter formation was accompanied by the inhibition of cell proliferation evidenced by a significant decrease in cell number, PCNA expression, and asymmetry of the ploidy histograms. A transient stimulation of apoptosis after 7 days of treatment was also observed. MMI administration stimulated TGF-beta1 but not TGF-beta3 synthesis. IL-delta alone caused a slight increase of TGF-beta3 but not TGF-beta1, whereas potassium iodide (KI) stimulated both isoforms and MMI reversed KI effect on TGF-beta1 expression but not on TGF-beta3. CONCLUSIONS: The goiter inhibitory action of IL-delta is due to the inhibition of cell proliferation and the transient stimulation of apoptosis. This latter action does not involve oxidative stress. TGF-beta1 does not play a role in the autoregulatory pathway mediated by IL-delta. Iodide stimulates TGF-beta3 without the need of being organified. These results suggest that there may be more than one pathway involved in the autoregulatory mechanism.

Oral potassium iodide for the treatment of sporotrichosis

            (Xue, Gu et al. 2009) Download

BACKGROUND: Sporotrichosis is a subacute or chronic disease, usually affecting the skin caused by a dimorphic (existing in two forms), aerobic (oxygen requiring) fungus called Sporothrix schenckii. Oral potassium iodide is widely used for cutaneous sporotrichosis in clinical medicine with more and more reports published. However, the benefits and adverse reactions of these treatments have not yet been systematically reviewed. OBJECTIVES: To assess the effects of oral potassium iodide for the treatment of sporotrichosis. SEARCH STRATEGY: In July 2009 we searched the Cochrane Skin Group Specialised Skin Register, the Cochrane Central Register of Controlled Clinical Trials (CENTRAL) in The Cochrane Library (Issue 3, 2009), MEDLINE and EMBASE, The Chinese Biomedical Database, CNKI, VIP, and ongoing trials registers. SELECTION CRITERIA: Randomised trials comparing orally administered iodide with placebo, or with another treatment. Studies about potassium iodide as an adjunct were excluded. DATA COLLECTION AND ANALYSIS: Two authors planned to independently assess trial quality and extract data. We also planned to collect adverse effects information from the trials where possible. MAIN RESULTS: In the absence of any suitable randomised placebo-controlled trials or comparisons with other treatments in this area, we were unable to assess the effects of oral potassium iodide. AUTHORS' CONCLUSIONS: The currently available evidence is insufficient to assess the potential for oral potassium iodide in the treatment of sporotrichosis.There is no high-quality evidence for or against oral potassium iodide as a treatment for sporotrichosis. Further randomised double-blind placebo-controlled trials are needed to define the efficacy and acceptability of these interventions.

Oral potassium iodide for the treatment of sporotrichosis

            (Xue and Li 2009) Download

Potassium Iodide is the antimycotic of choice for the treatment of cutaneous sporotrichosis, because of its efficacy, safety and low cost. We carried out a review of published studies on the benefits and adverse reactions of using SSKI (Saturated Solution Potassium Iodide) as treatment for sporotrichosis, but could not identify any well-designed clinical trails. There is an urgent need to conduct randomized double-blind placebo-controlled trials and critically assess usefulness of SSKI by using a standardize monitoring or an effective self-report system.

Interactions of vitamin A and iodine deficiencies: effects on the pituitary-thyroid axis

            (Zimmermann 2007) Download

Vitamin A (VA) deficiency (VAD) and the iodine deficiency disorders (IDD) affect > 30% of the global population and these deficiencies often coexist in vulnerable groups. VAD has multiple effects on the pituitary-thyroid axis; VA status modulates thyroid gland metabolism, peripheral metabolism of thyroid hormone, and production of thyrotropin (TSH) by the pituitary. Findings from Africa children indicate that VAD in severely-IDD-affected children increases TSH stimulation and thyroid size, and reduces risk for hypothyroidism. In children with VAD, the higher TSH concentrations in the face of higher circulating total thyroxine suggest central resistance to normal TSH suppression by thyroid hormone. In IDD- and VAD-affected children receiving iodized salt, concurrent VA supplementation improves iodine efficacy. Recent VA and iodine depletion studies in rats indicate moderate VAD alone has no measurable effect on the pituitary-thyroid axis; however, concurrent iodine deficiency (ID) and VAD produce more severe primary hypothyroidism than ID alone. Repletion studies in VA- and iodine-deficient animals suggest: 1) primary hypothyroidism in animals with concurrent moderate VAD and ID does not reduce the efficacy of high doses of oral VA; 2) VAD does not reduce the efficacy of dietary iodine to correct pituitary-thyroid axis dysfunction due to iodine deficiency; and 3) given alone, without iodine repletion, high-dose VA supplementation in combined VAD and ID may reduce thyroid hyperstimulation and reduce risk for goiter.

Povidone-iodine for herpes zoster

         (Shann 2004) Download

Use of 5% povidone-iodine aerosol for recurrent genital herpes

            (Tummon 1981) Download

Topical therapy for genital herpes

            (Tummon 1982) Download

Betadine for herpes simplex infection

         (Waters, Barton et al. 2006) Download

The clinical value of aciclovir, oral or topical, in the episodic treatment of recurrent herpes virus infection is limited. Betadine (povidone-iodine) could provide a cheap, effective alternative for managing symptomatic recurrences. We describe a case where povidone-iodine was used successfully to treat a recurrence of genital herpes simplex and review the literature supporting povidone-iodine in the treatment of genital tract infections.


References

Aranda, N., S. Sosa, et al. (2012). "Uptake and antitumoral effects of iodine and 6-iodolactone in differentiated and undifferentiated human prostate cancer cell lines." Prostate.

Boeynaems, J. M. and W. C. Hubbard (1980). "Transformation of arachidonic acid into an iodolactone by the rat thyroid." J Biol Chem 255(19): 9001-4.

Braverman, L. E. (1991). "Effects of iodine on thyroid function in man." Trans Am Clin Climatol Assoc 102: 143-51; discussion 151-2.

Edward, J. F. (1954). "Iodine Use in the Treatment and Prevention of Poliomyelitis." Manitoba Medical Review 34(6): 337.

Gartner, R., P. Rank, et al. (2010). "The role of iodine and delta-iodolactone in growth and apoptosis of malignant thyroid epithelial cells and breast cancer cells." Hormones (Athens) 9(1): 60-6.

Langer, R., C. Burzler, et al. (2003). "Influence of iodide and iodolactones on thyroid apoptosis. Evidence that apoptosis induced by iodide is mediated by iodolactones in intact porcine thyroid follicles." Exp Clin Endocrinol Diabetes 111(6): 325-9.

Nunez-Anita, R. E., O. Arroyo-Helguera, et al. (2009). "A complex between 6-iodolactone and the peroxisome proliferator-activated receptor type gamma may mediate the antineoplastic effect of iodine in mammary cancer." Prostaglandins Other Lipid Mediat 89(1-2): 34-42.

Pisarev, M. A., L. Krawiec, et al. (1994). "Studies on the goiter inhibiting action of iodolactones." Eur J Pharmacol 258(1-2): 33-7.

Rosner, H., P. Torremante, et al. (2010). "Antiproliferative/cytotoxic activity of molecular iodine and iodolactones in various human carcinoma cell lines. No interfering with EGF-signaling, but evidence for apoptosis." Exp Clin Endocrinol Diabetes 118(7): 410-9.

Sandhu, K. and S. Gupta (2003). "Potassium iodide remains the most effective therapy for cutaneous sporotrichosis." J Dermatolog Treat 14(4): 200-2.

Shann, F. (2004). "Povidone-iodine for herpes zoster." Lancet 364(9433): 502.

Thomasz, L., R. Oglio, et al. (2010). "Biochemical changes during goiter induction by methylmercaptoimidazol and inhibition by delta-iodolactone in rat." Thyroid 20(9): 1003-13.

Tummon, I. (1981). "Use of 5% povidone-iodine aerosol for recurrent genital herpes." Can Med Assoc J 124(10): 1257.

Tummon, I. S. (1982). "Topical therapy for genital herpes." Can Med Assoc J 127(9): 816.

Waters, L. J., S. E. Barton, et al. (2006). "Betadine for herpes simplex infection." Int J STD AIDS 17(12): 854-5.

Xue, S., R. Gu, et al. (2009). "Oral potassium iodide for the treatment of sporotrichosis." Cochrane Database Syst Rev(4): CD006136.

Xue, S. L. and L. Li (2009). "Oral potassium iodide for the treatment of sporotrichosis." Mycopathologia 167(6): 355-6.

Zimmermann, M. B. (2007). "Interactions of vitamin A and iodine deficiencies: effects on the pituitary-thyroid axis." Int J Vitam Nutr Res 77(3): 236-40.