Molecular iodine (I2) exhibits antiproliferative and apoptotic effects on in vivo and in vitro cancer models. These effects are thought to be mediated by an iodinated arachidonic acid derivative, 6-iodolactone (6IL), and one of the proposed mechanisms is that 6IL activates Peroxisome Proliferator-Activated Receptors type gamma (PPARG). These receptors have been implicated in the inhibition of carcinogenic processes, in addition to their classical role in maintaining lipid and glucose homeostasis. The aim of this study was to determine whether PPARG participates in the 6IL antiproliferative and apoptotic effects on the mammary cancer cell line MCF-7. The 6IL/PPARG complex was inhibited by the PPARG antagonist GW9662, in both an endogenous and overexpressed (adenoviral vector infection) context, and stable PPARG-knockdown MCF-7 cells (RNA interference, confirmed with hydrolysis probes and Western blot), were used to corroborate the PPARG participation. 6IL effects on proliferation (measured by Trypan Blue exclusion) and apoptosis (phosphatidylserine identification by flow cytometer) were evaluated in conditions of chemical inhibition (GW9662) and silencing (RNA interference). A wound-healing assay was conducted on wild-type and stable PPARG-knockdown MCF-7 cells to evaluate the antimigrational effect of 6IL. Caspase-8 activity was evaluated to determine if the extrinsic pathway is involved in the effects of 6IL and I2 treatment. Antiproliferative and pro-apoptotic 6IL effects require the activation of PPARG. In addition, wound-healing assays show that 6IL is able to inhibit MCF-7 cell migration and that PPARG plays a role in this phenomenon. Finally, the data exclude the participation of the extrinsic apoptotic pathway in 6IL- and I2-induced apoptosis. These results support the previously proposed mechanism, in which the I2 effects are mediated by 6IL, and they provide further support for the use of I2 as coadjuvant in breast cancer treatment.

The immune system is a crucial component in cancer progression or regression. Molecular iodine (I2) exerts significant antineoplastic effects, acting as a differentiation inductor and immune modulator, but its effects in antitumor immune response are not elucidated. The present work analyzed the effect of I2 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. In vitro analysis showed that the 200 μM I2 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 I2 supplement impairs implantation (incidence), tumoral growth, and proliferation of both types of cells. Xenografts of the animals treated with I2 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 I2 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. I2 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.

During embryonic and fetal development, the cerebellum undergoes several histological changes that require a specific microenvironment. Pleiotrophin (PTN) has been related to cerebral and cerebellar cortex ontogenesis in different species. PTN signaling includes PTPRZ1, ALK, and NRP-1 receptors, which are implicated in cell differentiation, migration, and proliferation. However, its involvement in human cerebellar development has not been described so far. Therefore, we investigated whether PTN and its receptors were expressed in the human cerebellar cortex during fetal and early neonatal development. The expression profile of PTN and its receptors was analyzed using an immunohistochemical method. PTN, PTPRZ1, and NRP-1 were expressed from week 17 to the postnatal stage, with variable expression among granule cell precursors, glial cells, and Purkinje cells. ALK was only expressed during week 31. These results suggest that, in the fetal and neonatal human cerebellum, PTN is involved in cell communication through granule cell precursors, Bergmann glia, and Purkinje cells via PTPRZ1, NRP-1, and ALK signaling. This communication could be involved in cell proliferation and cellular migration. Overall, the present study represents the first characterization of PTN, PTPRZ1, ALK, and NRP-1 expression in human tissues, suggesting their involvement in cerebellar cortex development.