Vitamin D receptor expression is associated with improved overall survival in human glioblastoma multiforme

Vitamin D and its analogs have been shown to display anti-proliferative effects in a wide variety of cancer types including glioblastoma multiforme (GBM). These anticancer effects are mediated by its active metabolite, 1α, 25-dihydroxyvitamin D3 (calcitriol) acting mainly through vitamin D receptor (VDR) signaling. In addition to its involvement in calcitriol action, VDR has also been demonstrated to be useful as a prognostic factor for some types of cancer. However, to our knowledge, there are no studies evaluating the expression of VDR protein and its association with outcome in gliomas. Therefore, we investigated VDR expression by using immunohistochemical analysis in human glioma tissue microarrays, and analyzed the association between VDR expression and clinico-pathological parameters. We further investigated the effects of genetic and pharmacologic modulation of VDR on survival and migration of glioma cell lines. Our data demonstrate that VDR is increased in tumor tissues when compared with VDR in non-malignant brains, and that VDR expression is associated with an improved outcome in patients with GBM. We also show that both genetic and pharmacologic modulation of VDR modulates GBM cellular migration and survival and that VDR is necessary for calcitriol-mediated effects on migration. Altogether these results provide some limited evidence supporting a role for VDR in glioma progression.Fil: Salomón, Débora Gisele. Consejo Nacional de Investigaciones Cienti­ficas y Tecnicas. Centro Cientifico Tecnologico Bahi­a Blanca. Instituto de Investigaciones Bioquimicas Bahi­a Blanca (i); ArgentinaFil: Fermento, María Eugenia. Consejo Nacional de Investigaciones Cienti­ficas y Tecnicas. Centro Cientifico Tecnologico Bahi­a Blanca. Instituto de Investigaciones Bioquimicas Bahi­a Blanca (i); ArgentinaFil: Gandini, Norberto Ariel. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Bahi­a Blanca. Instituto de Investigaciones Bioquimicas Bahi­a Blanca (i); ArgentinaFil: Ferronato, María Julia. Consejo Nacional de Investigaciones Cienti­ficas y Tecnicas. Centro Cientifico Tecnologico Bahi­a Blanca. Instituto de Investigaciones Bioquimicas Bahi­a Blanca (i); ArgentinaFil: Arevalo, Julian. Hospital Municipal General de Agudos Doctor José Penna; ArgentinaFil: Blasco, J.. Hospital Int. Gral. de Agudos Dr. Jose Penna. Servicio de Patologia; ArgentinaFil: Andrés, Nancy Carolina. Consejo Nacional de Investigaciones Cienti­ficas y Tecnicas. Centro Cientifico Tecnologico Bahi­a Blanca. Instituto de Investigaciones Bioquimicas Bahi­a Blanca (i); ArgentinaFil: Zenklusen, Jean C.. National Institutes of Health. National Cancer Institute; Estados UnidosFil: Curino, Alejandro Carlos. Consejo Nacional de Investigaciones Cienti­ficas y Tecnicas. Centro Cientifico Tecnologico Bahi­a Blanca. Instituto de Investigaciones Bioquimicas Bahi­a Blanca (i); ArgentinaFil: Facchinetti, Maria Marta. Consejo Nacional de Investigaciones Cienti­ficas y Tecnicas. Centro Cientifico Tecnologico Bahi­a Blanca. Instituto de Investigaciones Bioquimicas Bahi­a Blanca (i); Argentin

Cultivos diseñados por ingeniería genética: Una alternativa atractiva para la producción de biocombustibles. Parte I

Hoy en día, herramientas como la ingeniería genética y el mejoramiento molecular han permitido modificar los cultivos. Los desafíos incluyen desde encontrar nuevos cultivos alternativos, capaces de reemplazar a la soja y el maíz en la producción de diésel y etanol, hasta modificar genéticamente los cultivos tradicionales para obtener mayor rendimiento o mejor calidad. La posición de nuestro país en la producción de los biocombustibles.Fil: Luciani, Gabriela Fabiana. Universidad Nacional del Sur. Departamento de Agronomía; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Díaz, Marina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Martinez Macias, Félix. Universidad de Valencia; EspañaFil: Salomón, Débora Gisele. Universidad Nacional del Sur. Departamento de Agronomía; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Echenique, Carmen Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; Argentin

Phosphonate analogues of 1, 25 dihydroxyvitamin D3 are promising candidates for antitumoural therapies

The active metabolite of vitamin D, 1α, 25 dihydroxyvitamin D3 (calcitriol) is classically known to regulate calcium and phosphate homeostasis and bone mineralization. In addition, calcitriol has also been documented to act as a potent anticancer agent in multiple cell culture and animal models of cancer. However, major side effects, such as hypercalcemia, hinder broad-spectrum therapeutic uses of calcitriol in cancer chemotherapy. Synthesis of calcitriol analogues with the same or increased antiproliferative and pro-differentiating activities, and with reduced undesired effects on calcium and bone metabolism, is getting significant attention towards rational therapeutics to treat cancer. In this regard, phosphonate analogues have been shown to display a certain degree of dissociation between the vitamin D activity in vitro and undesired hypercalcemia in vivo. However, few phosphonates have been described in the literature and fewer of them tested for antitumoral effects. Our group has synthesized a novel vitamin D analogue (EM1) bearing an alkynylphosphonate moiety that combines the low calcemic properties of phosphonates with the decreased metabolic inactivation due to the presence of a triple bond between C-23 and C-24. Biological assays demonstrated that this analogue has potent antiproliferative effects in a wide panel of tumour cell lines, even in those resistant to calcitriol treatment. Importantly, EM1 does not show toxic effects in animals, even administered at high doses and for extended periods of time. In the current review we discuss the effects and the potential application in cancer of vitamin D and its derivatives, with an emphasis on phosphonate analogues.Fil: Salomón, Débora Gisele. Consejo Nacional de Investigaciones Cientificas y T__etilde__cnicas. Centro Cient__itilde__fico Tecnol__otilde__gico Bahia Blanca. Instituto de Investigaciones Bioqu__itilde__micas Bahia Blanca (i); ArgentinaFil: Mascaro, Evangelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; ArgentinaFil: Grioli, Silvina Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Consejo Nacional de Investigaciones Cientificas y Técnicas. Centro Científico Tecnológico Bahia Blanca. Instituto de Investigaciones Bioquímicas Bahia Blanca (i); ArgentinaFil: Ferronato, María Julia. Consejo Nacional de Investigaciones Cientificas y T__etilde__cnicas. Centro Cient__itilde__fico Tecnol__otilde__gico Bahia Blanca. Instituto de Investigaciones Bioqu__itilde__micas Bahia Blanca (i); ArgentinaFil: Vitale, Cristian Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; ArgentinaFil: Radivoy, Gabriel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; ArgentinaFil: Curino, Alejandro Carlos. Consejo Nacional de Investigaciones Cientificas y T__etilde__cnicas. Centro Cient__itilde__fico Tecnol__otilde__gico Bahia Blanca. Instituto de Investigaciones Bioqu__itilde__micas Bahia Blanca (i); ArgentinaFil: Facchinetti, Maria Marta. Consejo Nacional de Investigaciones Cientificas y T__etilde__cnicas. Centro Cient__itilde__fico Tecnol__otilde__gico Bahia Blanca. Instituto de Investigaciones Bioqu__itilde__micas Bahia Blanca (i); Argentin

Synthesis and biological evaluation of a new vitamin D2 analogue

A new vitamin D2 analogue was synthesized using the Julia-Kocienski olefination. It has antiproliferative effects on cell lines from squamous cell carcinomas of colon and head and neck, but is also as hypercalcaemic as calcitriol in vivoFil: Gándara, Zoila. Universidad de Vigo. Facultad de Ciencias; EspañaFil: Pérez, Manuel. Universidad de Vigo. Facultad de Ciencias; EspañaFil: Salomón, Débora Gisele. Consejo Nacional de Investigaciones Cientificas y T__etilde__cnicas. Centro Cient__itilde__fico Tecnol__otilde__gico Bahia Blanca. Instituto de Investigaciones Bioqu__itilde__micas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Ferronato, María Julia. Consejo Nacional de Investigaciones Cientificas y Técnicas. Centro Científico Tecnológico Bahia Blanca. Instituto de Investigaciones Bioquímicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Fermento, María Eugenia. Consejo Nacional de Investigaciones Cientificas y T__etilde__cnicas. Centro Cient__itilde__fico Tecnol__otilde__gico Bahia Blanca. Instituto de Investigaciones Bioqu__itilde__micas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Curino, Alejandro Carlos. Consejo Nacional de Investigaciones Cientificas y T__etilde__cnicas. Centro Cient__itilde__fico Tecnol__otilde__gico Bahia Blanca. Instituto de Investigaciones Bioqu__itilde__micas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Facchinetti, Maria Marta. Consejo Nacional de Investigaciones Cientificas y T__etilde__cnicas. Centro Cient__itilde__fico Tecnol__otilde__gico Bahia Blanca. Instituto de Investigaciones Bioqu__itilde__micas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Gómez, Generosa. Universidad de Vigo. Facultad de Ciencias; EspañaFil: Fall, Yagamare. Universidad de Vigo. Facultad de Ciencias; Españ

Nuclear Heme oxygenase-1 is associated to tumor progression in Human Head and Neck Carcinoma.

The expression of heme oxygenase-1 (HO-1) was shown to be increased in multiple tumors compared with their surrounding healthy tissues and was also observed to be up-regulated in oral squamous cell carcinomas (OSCC). However, conflicting results were obtained and little information is available regarding HO-1 significance in head and neck squamous cell carcinoma (HNSCC). Therefore, the aim of the present study was to perform a wide screening of HO-1 expression in a large collection of human primary HNSCCs and to correlate the results with clinical and pathological parameters. For this purpose, we investigated the expression of this protein by immunohistochemistry (IHC) in tissue microarrays (TMAs) of HNSCC and in an independent cohort of paraffin-embedded tumor specimens. HO-1 expression was further validated by real-time qPCR performed on selected laser capture-microdissected (LCM) oral tissue samples. Both the number of HO-1-positive samples and HO-1 immunoreactivity in the cancerous tissues were significantly higher than those in the non-tumor tissues. These results were confirmed at the mRNA level. Interestingly, HO-1 localization was observed in the nucleus, and the rate of nuclear HO-1 in HNSCC was higher than that in non-malignant tissues. Nuclear HO-1 was observed in HNSCC cell lines and increased even further following hemin treatment. Analysis of HO-1 expression and sub-cellular localization in a mouse model of squamous cell carcinoma (SCC) and in human HNSCC revealed that nuclear HO-1 increases with tumor progression. Taken together, these results demonstrate that HO-1 is up-regulated in HNSCC and that nuclear localization of HO-1 is associated with malignant progression in this tumor type.Fil: Gandini, Norberto Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Fermento, María Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Salomón, Débora Gisele. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Blasco, Jorge. Servicio de Patología del Hospital Dr José Penna; Argentina. Hospital Municipal General de Agudos Doctor José Penna; ArgentinaFil: Patel, Vyomesh. National Institutes of Health; Estados UnidosFil: Gutkind, J. Silvio. National Institutes of Health; Estados UnidosFil: Molinolo, Alfredo. National Institutes of Health; Estados UnidosFil: Facchinetti, Maria Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Curino, Alejandro Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentin

Heme oxygenase-1 expression in human gliomas and its correlation with poor prognosis in patients with astrocytoma

In human glioma tumors, heme oxygenase-1 (HO-1) has been shown to be upregulated both when compared with normal brain tissues and also during oligodendroglioma progression. The cell types that express HO-1 have been shown to be mainly macrophages/microglia and T cells. However, many other reports also demonstrated that cell lines derived from glioma tumors and astrocytes express HO-1 after the occurrence of a wide variety of cell injuries and stressors. In addition, the significance of HO-1 upregulation in glioma had not, so far, been addressed. We therefore aimed at investigating the expression and significance of HO-1 in human glial tumors. For this purpose, we performed a wide screening of HO-1 expression in gliomas by using tissue microarrays containing astrocytomas, oligodendrogliomas, mixed tumors, and normal brain tissues. We subsequently correlated protein expression with patient clinicopathological data. We found differences in HO-1 positivity rates between non-malignant brain (22 %) and gliomas (54 %, p = 0.01). HO-1 was expressed by tumor cells and showed cytoplasmic localization, although 19 % of tumor samples also depicted nuclear staining. Importantly, a significant decrease in the overall survival time of grade II and III astrocytoma patients with HO-1 expression was observed. This result was validated at the mRNA level in a cohort of 105 samples. However, no association of HO-1 nuclear localization with patient survival was detected. In vitro experiments aimed at investigating the role of HO-1 in glioma progression showed that HO-1 modulates glioma cell proliferation, but has no effects on cellular migration. In conclusion, our results corroborate the higher frequency of HO-1 protein expression in gliomas than in normal brain, demonstrate that HO-1 is expressed by glial malignant cells, and show an association of HO-1 expression with patients’ shorter survival time.Fil: Gandini, Norberto Ariel. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Fermento, María Eugenia. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Salomón, Débora Gisele. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Obiol, Diego Javier. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Andrés, Nancy Carolina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Zenklusen, Jean C.. National Institute of Health.The Cancer Genome Atlas Program Office; Estados UnidosFil: Arevalo, Julian. Hospital Municipal General de Agudos Doctor José Penna; ArgentinaFil: Blasco, Jorge. Hospital Municipal General de Agudos Doctor José Penna; ArgentinaFil: Lopez, Alejandro. Laboratorios IACA, Bahia Blanca; ArgentinaFil: Facchinetti, Maria Marta. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; ArgentinaFil: Curino, Alejandro Carlos. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina. Universidad Nacional del Sur; Argentin

Antitumoral effects of the alkynylphosphonate analogue of calcitriol EM1 on glioblastoma multiforme cells

Glioblastoma multiforme (GBM) is the worst and most common brain tumor, characterized by high proliferation and invasion rates. The current standard treatment is mainly based on chemoradiotherapy and this approach has slightly improved patient survival. Thus, novel strategies aimed at prolonging the survival and ensuring a better quality of life are necessary. In the present work, we investigated the antitumoral effect of the novel analogue of calcitriol EM1 on GBM cells employing in vitro, in silico, and in vivo assays. In vitro, we demonstrated that EM1 treatment selectively decreases the viability of murine and human tumor cells without affecting that of normal human astrocytes. The analysis of the mechanisms showed that EM1 produces cell cycle arrest in the T98G cell line, which is accompanied by an increase in p21, p27, p57 protein levels and a decrease in cyclin D1, p-Akt-S473, p-ERK1/2 and c-Jun expression. Moreover, EM1 treatment also exerts in GBM cells anti-migratory effects and decreases their invasive capacity by a reduction in MMP-9 proteolytic activity. In silico, we demonstrated that EM1 is able to bind to the vitamin D receptor with greater affinity than calcitriol. Finally, we showed that EM1 treatment of nude mice administered at 50 ug/Kg body weight during 21 days neither induces hypercalcemia nor toxicity effects. In conclusion, all the results indicate the potential of EM1 analogue as a promising therapeutic alternative for GBM treatment.Fil: Ferronato, María Julia. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Alonso, Eliana Noelia. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Salomón, Débora Gisele. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Fermento, María Eugenia. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Gandini, Norberto Ariel. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Mascaro, Evangelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Vitale, Cristian Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Fall, Yagamare. Universidad de Vigo. Facultad de Ciencias; EspañaFil: Facchinetti, Maria Marta. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Curino, Alejandro Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentin

Inhibition of p300 suppresses growth of breast cancer. Role of p300 subcellular localization

There is evidence that p300, a transcriptional co-factor and a lysine acetyl-transferase, could play a role both as an oncoprotein and as a tumor suppressor, although little is known regarding its role in breast cancer (BC). First we investigated the role p300 has on BC by performing pharmacological inhibition of p300 acetyl-transferase function and analyzing the effects on cell count, migration and invasion in LM3 murine breast cancer cell line and on tumor progression in a syngeneic murine model. We subsequently studied p300 protein expression in human BC biopsies and evaluated its correlation with clinical and histopathological parameters of the patients. We observed that inhibition of p300 induced apoptosis and reduced migration and invasion in cultured LM3 cells. Furthermore, a significant reduction in tumor burden, number of lung metastases and number of tumors invading the abdominal cavity was observed in a syngeneic tumor model of LM3 following treatment with the p300 inhibitor. This reduction in tumor burden was accompanied by a decrease in the mitotic index and Ki-67 levels and an increase in Bax expression. Moreover, the analysis of p300 expression in human BC samples showed that p300 immunoreactivity is significantly higher in the cancerous tissues than in the non-malignant mammary tissues and in the histologically normal adjacent tissues. Interestingly, p300 was observed in the cytoplasm, and the rate of cytoplasmic p300 was higher in BC than in non-tumor tissues. Importantly, we found that cytoplasmic localization of p300 is associated with a longer overall survival time of the patients. In conclusion, we demonstrated that inhibition of the acetylase function of p300 reduces both cell count and invasion in LM3 cells, and decreases tumor progression in the animal model. In addition, we show that the presence of p300 in the cytoplasm correlates with increased survival of patients suggesting that its nuclear localization is necessary for the pro-tumoral effects.Fil: Fermento, María Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); ArgentinaFil: Gandini, Norberto Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); ArgentinaFil: Salomón, Débora Gisele. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); ArgentinaFil: Ferronato, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); ArgentinaFil: Vitale, Cristian Alejandro. Universidad Nacional del Sur. Departamento de Química; ArgentinaFil: Arevalo, Julian. Hospital Int. Gral. de Agudos Dr. Jose Penna. Servicio de Patologia; ArgentinaFil: Lopez Romero, Alejandro. Laboratorios IACA. Departamento de Hematología; ArgentinaFil: Nuñez, Myriam Carmen. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Físico Matemática; ArgentinaFil: Jung, Manfred. Albert-Ludwigs University Freiburg. Institute of Pharmaceutical Sciences; AlemaniaFil: Facchinetti, Maria Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); ArgentinaFil: Curino, Alejandro Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); Argentin

The alkynylphosphonate analogue of calcitriol EM1 has potent anti-metastatic effects in breast cancer

The active form of vitamin D3, calcitriol, plays a major role in maintaining calcium/phosphate homeostasis. In addition, it is a potent antiproliferative and prodifferentiating agent. However, when effective antitumor doses of calcitriol are employed, hypercalcemic effects are observed, thus precluding its therapeutic application. To overcome this problem, structural analogues have been designed with the aim at retaining or even increasing the antitumor effects while decreasing its calcemic activity. This report shows the biological evaluation of an alkynylphosphonate vitamin D less-calcemic analogue in amurine model of breast cancer. We demonstrate that this compound has potent anti-metastatic effects through its action over cellular migration and invasion likely mediated through the up-regulation of Ecadherin expression. Based on the current in vitro and in vivo results, EM1 is a promising candidate as atherapeutic agent in breast cancer.Fil: Ferronato, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); ArgentinaFil: Obiol, Diego Javier. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.Bioquimicas Bahia Blanca (i); ArgentinaFil: Fermento, María Eugenia. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.Bioquimicas Bahia Blanca (i); ArgentinaFil: Gandini, Norberto Ariel. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.Bioquimicas Bahia Blanca (i); ArgentinaFil: Alonso, Eliana Noelia. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.Bioquimicas Bahia Blanca (i); ArgentinaFil: Salomón, Débora Gisele. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.Bioquimicas Bahia Blanca (i); ArgentinaFil: Vitale, Cristian Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; ArgentinaFil: Mascaro, Evangelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; ArgentinaFil: Fall, Yagamare. Universidad de Vigo; EspañaFil: Raimondi, Ana Rosa. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología; ArgentinaFil: Curino, Alejandro Carlos. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); ArgentinaFil: Facchinetti, Maria Marta. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentin