Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is upregulated in several cervix cancer cell lines as well as in carcinomas of the uterine cervix. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and exhibit antiproliferative effects on cervix cancer cells. Chemical library screening was used to identify hit compounds, which were further prioritized in profiling and kinetic experiments. SAR analysis was applied in the search for analogs with improved potency and selectivity, resulting in the discovery of novel inhibitors that are able to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR’s active site. This multidentate binding mode was confirmed by Xray crystallography. The inhibitors decreased the proliferation of cervix cancer cells, while growth of primary normal keratinocytes was not affected. These compounds may be a starting point to develop drugs for the treatment of cervical cancer.

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The evidence shows that probiotics can reduce cardiovascular diseases associated to high cholesterol levels, but it occurs just when they survive gastrointestinal conditions. The aim of this study was to evaluate the ability of reference strains (RS) and food isolates strains (FIS) to survive acid and bile and to determine in-vitro cholesterol assimilation. FIS were more tolerant to acid than RS, showing significantly different growth response. FIS were more resistant to the presence of bile, in order descendent to oxgall, taurocholic acid, and cholic acid. The survival percentages ranged from 0% to 100%, presenting strain dependence. The most tolerant strains were tested for cholesterol test, showing RS lower percentages than FIS. In FIS, the percentage was negatively affected when the concentration of bile salt was increased. Therefore, to study the viability of different strains in gastrointestinal conditions is crucial because of the strain-dependence nature.Asimilación de colesterol y supervivencia al ácido y bilis de bacterias probióticas aisladas de alimentos y cepas de referencia RESUMEN La evidencia científica muestra que los probióticos pueden reducer enfermedades cardiovasculares asociadas a altos niveles de colesterol pero sólo cuando sobreviven a condiciones gastrointestinales. El objetivo del estudio fue evaluar la supervivencia a ácido y bilis de cepas aisladas de alimentos (FIS) y de referencia (RS) y determinar in vitro, su asimilación de colesterol. FIS mostraron mayor tolerancia al ácido que RS, mostrando diferencias significativas en el crecimiento. FIS mostró mayor resistencia a la bilis; en orden descendente: oxgall, ácido taurocólico y ácido cólico. El porcentaje de supervivencia fue 0-100%, siendo cepa dependiente. Las cepas más tolerantes fueron evaluadas para su asimilación de colesterol, mostrando RS menores porcentajes que FIS. En éstas, el porcentaje fue afectado negativamente al incrementar la concentración de la sal biliar. Por lo tanto, es importante evaluar la viabilidad de las cepas en condiciones intestianles por su caracter cepadependiente. ARTICLE HISTORY

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