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Neuroblastoma (NB) is the most common solid childhood tumor, and all-trans retinoic acid (ATRA) is used as a treatment to decrease minimal residual disease. Molecular iodine (I2) induces differentiation and/or apoptosis in several neoplastic cells through activation of PPARγ nuclear receptors. Here, we analyzed whether the coadministration of I2 and ATRA increases the efficacy of NB treatment. ATRA-sensitive (SH-SY5Y), partially-sensitive (SK-N-BE(2)), and non-sensitive (SK-N-AS) NB cells were used to analyze the effect of I2 and ATRA in vitro and in xenografts (Foxn1 nu/nu mice), exploring actions on cellular viability, differentiation, and molecular responses. In the SH-SY5Y cells, 200 μM I2 caused a 100-fold (0.01 µM) reduction in the antiproliferative dose of ATRA and promoted neurite extension and neural marker expression (tyrosine hydroxylase (TH) and tyrosine kinase receptor alpha (Trk-A)). In SK-N-AS, the I2 supplement sensitized these cells to 0.1 μM ATRA, increasing the ATRA-receptor (RARα) and PPARγ expression, and decreasing the Survivin expression. The I2 supplement increased the mitochondrial membrane potential in SK-N-AS suggesting the participation of mitochondrial-mediated mechanisms involved in the sensibilization to ATRA. In vivo, oral I2 supplementation (0.025%) synergized the antitumor effect of ATRA (1.5 mg/kg BW) and prevented side effects (body weight loss and diarrhea episodes). The immunohistochemical analysis showed that I2 supplementation decreased the intratumoral vasculature (CD34). We suggest that the I2 + ATRA combination should be studied in preclinical and clinical trials to evaluate its potential adjuvant effect in addition to conventional treatments.

This study analyzes an oral supplement of molecular iodine (I 2 ), alone and in combination with the neoadjuvant therapy 5-fluorouracil/epirubicin/cyclophosphamide or taxotere/epirubicin (FEC/TE) in women with Early (stage II) and Advanced (stage III) breast cancer. In the Early group, 30 women were treated with I 2 (5 mg/day) or placebo (colored water) for 7-35 days before surgery. For the Advanced group, 30 patients received I 2 or placebo, along with FEC/TE treatment. After surgery, all patients received FEC/TE + I 2 for 170 days. I 2 supplementation showed a significant attenuation of the side effects and an absence of tumor chemoresistance. The control, I 2 , FEC/TE, and FEC/TE + I 2 groups exhibited response rates of 0, 33%, 73%, and 100%, respectively, and a pathologic complete response of 18%, and 36% in the last two groups. Five-year disease-free survival rate was significantly higher in patients treated with the I 2 supplement before and after surgery compared to those receiving the supplement only after surgery (82% versus 46%). I 2 -treated tumors exhibit less invasive potential, and significant increases in apoptosis, estrogen receptor expression, and immune cell infiltration. Transcriptomic analysis indicated activation of the antitumoral immune response. The results led us to register a phase III clinical trial to analyze chemotherapy + I 2 treatment for advanced breast cancer.

Background: The immune system is a crucial component in cancer progression or regression. Molecular iodine (I 2 ) exerts significant antineoplastic effects, acting as a differentiation inductor and immune modulator, but its effects in antitumor immune response are not elucidated., Methods: The present work analyzed the effect of I 2 in human breast cancer cell lines with low (MCF-7) and high (MDA-MB231) metastatic potential under both in vitro (cell proliferation and invasion assay) and in vivo (xenografts of athymic nude mice) conditions., Results: In vitro analysis showed that the 200 μM I 2 supplement decreases the proliferation rate in both cell lines and diminishes the epithelial-mesenchymal transition (EMT) profile and the invasive capacity in MDA-MB231. In immunosuppressed mice, the I 2 supplement impairs implantation (incidence), tumoral growth, and proliferation of both types of cells. Xenografts of the animals treated with I 2 decrease the expression of invasion markers like CD44, vimentin, urokinase plasminogen activator and its receptor, and vascular endothelial growth factor; and increase peroxisome proliferator-activated receptor gamma. Moreover, in mice with xenografts, the I 2 supplement increases the circulating level of leukocytes and the number of intratumoral infiltrating lymphocytes, some of them activated as CD8+, suggesting the activation of antitumor immune responses., Conclusions: I 2 decreases the invasive potential of a triple negative basal cancer cell line, and under in vivo conditions the oral supplement of this halogen activates the antitumor immune response, preventing progression of xenografts from laminal and basal mammary cancer cells. These effects allow us to propose iodine supplementation as a possible adjuvant in breast cancer therapy.

Background: Mammary cancer has a high incidence in canines and is an excellent model of spontaneous carcinogenesis. Molecular iodine (I 2 ) exerts antineoplastic effects on different cancer cells activating re-differentiation pathways. In co-administration with anthracyclines, I 2 impairs chemoresistance installation and prevents the severity of side effects generated by these antineoplastic drugs. This study is a random and double-blind protocol that analyzes the impact of I 2 (10 mg/day) in two administration schemes of Doxorubicin (DOX; 30 mg/m2) in 27 canine patients with cancer of the mammary gland. The standard scheme (sDOX) includes four cycles of DOX administered intravenously for 20 min every 21 days, while the modified scheme (mDOX) consists of more frequent chemotherapy (four cycles every 15 days) with slow infusion (60 min). In both schemes, I 2 or placebo (colored water) was supplemented daily throughout the treatment., Results: mDOX attenuated the severity of adverse events (VCOG-CTCAE) in comparison with the sDOX group. The overall tumor response rate (RECIST criteria) for all dogs was 18% (interval of reduction 48-125%), and no significant difference was found between groups. I 2 supplementation enhances the antineoplastic effect in mDOX, exhibiting a significant decrease in the tumor epithelial fraction, diminished expression of chemoresistance (MDR1 and Survivin) and invasion (uPA) markers and enhanced expression of the differentiation factor known as peroxisome proliferator-activated receptors type gamma (PPARγ). Significant tumor lymphocytic infiltration was also observed in both I 2 -supplemented groups. The ten-month survival analysis showed that the entire I 2 supplementation (before and after surgery) induced 67-73% of disease-free survival, whereas supplementation in the last period (only after surgery) produced 50% in both schemes., Conclusions: The mDOX+I 2 scheme improves the therapeutic outcome, diminishes the invasive capacity, attenuates the adverse events and increases disease-free survival. These data led us to propose mDOX+I 2 as an effective treatment for canine mammary cancer.

Oxidative stress and inflammation are involved in the development and/or progression of benign prostatic hyperplasia (BPH). Molecular iodine (I 2 ) induces antiproliferative and apoptotic effects in prostate cancer cells, but it is unknown if I 2 regulates oxidative stress in the normal and/or tumoral prostate. The purpose of this study was to analyze the effects of I 2 and celecoxib (Cxb) on oxidative stress and inflammation in a model of prostatic hyperplasia. Cxb was used as positive control of cyclooxygenase-2 (COX-2) inhibition. Prostatic hyperplasia was induced in male Wistar rats (170g) with testosterone (5mg/kg/week, for three weeks). One week before hyperplasia induction, I 2 (25mg/day/rat) or Cxb (1.25mg/day/rat) was supplied for four weeks in the drinking water. Prostatic hyperplasia was evaluated by histological analysis, DNA content, and/or proliferating cell nuclear antigen (PCNA) expression. Lipoperoxidation (malondialdehyde) and nitrite (NO2 - ) levels were analyzed by colorimetric methods, while nitric oxide synthase (NOS), COX, and myeloperoxidase (MPO) enzymes were analyzed using RT-PCR, immunoblotting, and/or enzymatic assays. Levels of 15-F2t-isoprostanes, prostaglandins (PGE 2 ), leukotrienes (LTB 4 ), and tumor necrosis factor alpha (TNFα) were measured by ELISA. Control testosterone-treated animals exhibited hyperplasia in the dorsolateral prostate, as well as increments in almost all oxidative parameters except for COX-1, TNFα, or MPO. I 2 and Cxb prevented epithelial hyperplasia (DNA content) and oxidative stress induction generated by testosterone in almost the same intensity, and the minimum I 2 dose required was 2.5mg/rat. The antioxidant capacity of I 2 was also analyzed in a cell-free system, showing that this element inhibited the conversion of nitrate (NO 3 - ) to NO 2 - . I 2 did not modify the prostatic oxidative state in testosterone untreated rats. In summary, our data showed that antiproliferative and antioxidant effects of I 2 involve the inhibition of NOS and the COX-2 pathway. Further studies are necessary to analyze the therapeutic and/or adjuvant effects of I 2 with first-line medications used to treat BPH., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Iodine supplementation exerts antitumor effects in several types of cancer. Iodide (I⁻) and iodine (I₂) reduce cell proliferation and induce apoptosis in human prostate cancer cells (LNCaP and DU-145). Both chemical species decrease tumor growth in athymic mice xenografted with DU-145 cells. The aim of this study was to analyze the uptake and effects of iodine in a preclinical model of prostate cancer (transgenic adenocarcinoma of the mouse prostate [TRAMP] mice/SV40-TAG antigens), which develops cancer by 12 wks of age. ¹²⁵I⁻ and ¹²⁵I₂ uptake was analyzed in prostates from wild-type and TRAMP mice of 12 and 24 wks in the presence of perchlorate (inhibitor of the Na⁺/I⁻ symporter [NIS]). NIS expression was quantified by quantitative polymerase chain reaction (qPCR). Mice (6 wks old) were supplemented with 0.125 mg I⁻ plus 0.062 mg I₂/mouse/day for 12 or 24 wks. The weight of the genitourinary tract (GUT), the number of acini with lesions, cell proliferation (levels of proliferating cell nuclear antigen [PCNA] by immunohistochemistry), p53 and p21 expression (by qPCR) and apoptosis (relative amount of nucleosomes by enzyme-linked immunosorbent assay) were evaluated. In both age-groups, normal and tumoral prostates take up both forms of iodine, but only I⁻ uptake was blocked by perchlorate. Iodine supplementation prevented the overexpression of NIS in the TRAMP mice, but had no effect on the GUT weight, cell phenotype, proliferation or apoptosis. In TRAMP mice, iodine increased p53 expression but had no effect on p21 (a p53-dependent gene). Our data corroborate NIS involvement in I⁻ uptake and support the notion that another transporter mediates I₂ uptake. Iodine did not prevent cancer progression. This result could be explained by a strong inactivation of the p53 pathway by TAG antigens.

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., (Copyright © 2012 Wiley Periodicals, Inc.)

Several groups, including ours, have reported that iodine exhibited antiproliferative and apoptotic effects in various cancer cells only if this element is supplemented as molecular iodine, or as iodide, to cells that are able to oxidize it with the enzyme thyroperoxidase. In this study, we analyzed the effect of various concentrations of iodine and/or iodide in the dimethylbenz[a]anthracene (DMBA) mammary cancer model in rats. The results show that 0.1% iodine or iodide increases the expression of peroxisome proliferator-activated receptor type γ (PPARγ), triggering caspase-mediated apoptosis pathways in damaged mammary tissue (DMBA-treated mammary gland) as well as in frank mammary tumors, but not in normal mammary gland. DMBA treatment induces the expression of lactoperoxidase, which participates in the antineoplastic effect of iodide and could be involved in the pro-neoplastic effect of estrogens, increasing the formation of DNA adducts. In conclusion, our results show that a supplement of 0.1% molecular iodine/potassium iodide (0.05/0.05%) exert antineoplastic effects, preventing estrogen-induced DNA adducts and inducing apoptosis through PPARγ/caspases in pre-cancer and cancerous cells. Since this iodine concentration does not modify the cytology (histology, apoptosis rate) or physiology (triiodothyronine and thyrotropin) of the thyroid gland, we propose that it be considered as an adjuvant treatment for premenopausal mammary cancer.

Introduction: Studies in mammary cancer demonstrated that moderately high concentrations of molecular iodine (I2) have a antiproliferative and apoptotic effect either in vivo as in vitro, however the cellular intermediated involved in these effects has not been elucidated., Methods: Virgin Sprague-Dawley rats were treated with methyl-nitrosourea (MNU: single dose ip, 50 mg/Kg bw) and the participation of arachidonic acid (AA) and PPAR receptors in the antineoplasic effect of I2 where analyzed., Results: I2-treated rats for four weeks exhibited a significant reduction in the incidence (62.5 vs. 100%) and size (0.87 +/- 0.98 vs 1.96 +/- 1.5 cm3) of mammary tumors. HPLC analysis showed that tumoral but not normal mammary tissue contained an elevated basal concentration of AA and significantly more AA-iodinated called 6-iodolactone (6-IL) after chronic I2 treatment. Tumors from I2-treated rats showed fewer cells positive to proliferating cell nuclear antigen, lower blood vessel density, as well as decreases in vascular endothelial growth factor, urokinase-type plasminogen activator, and PPAR type alpha (PPARalpha). These same tumors showed increases in the cell death markers, TUNEL-positive cells (p < 0.05) and the enzyme caspase-3 (trend), as well as significant induction of PPAR type gamma (PPARgamma)., Conclusion: Together, these data demonstrate that the antineoplasic effect of iodine involves 6-IL formation and PPARgamma induction.