Although several epidemiologic studies show an association between arsenic exposure and prostate cancer, it is still unknown whether human prostate epithelial cells are directly susceptible to arsenic-induced transformation. This study was designed to determine whether the nontumorigenic human prostate epithelial cell line RWPE-1 could be malignantly transformed in vitro by arsenite. RWPE-1 cells were continuously exposed to 5 micro M arsenite and monitored for signs of transformation, assessed as changes in matrix metalloproteinase-9 levels. After 29 weeks of exposure, the arsenite-exposed RWPE-1 cells (referred to as CAsE-PE) showed a marked increase in matrix metalloproteinase-9 secretion, a common finding in prostate malignancies. Malignant transformation was confirmed when CAsE-PE cells produced aggressive undifferentiated malignant epithelial tumors in nude mice. The tumors stained positive for human prostate-specific antigen, confirming their origin. These results are the first report of arsenite-induced malignant transformation of a human epithelial cell line and provide an important in vitro model for studying the mechanisms underlying arsenic-induced carcinogenesis in humans.

A high calorie intake can induce the appearance of the metabolic syndrome (MS), which is a serious public health problem because it affects glucose levels and triglycerides in the blood. Recently, it has been suggested that MS can cause complications in the brain, since chronic hyperglycemia and insulin resistance are risk factors for triggering neuronal death by inducing a state of oxidative stress and inflammatory response that affect cognitive processes. This process, however, is not clear. In this study, we evaluated the effect of the consumption of a high-calorie diet (HCD) on both neurodegeneration and spatial memory impairment in rats. Our results demonstrated that HCD (90 day consumption) induces an alteration of the main energy metabolism markers, indicating the development of MS in rats. Moreover, an impairment of spatial memory was observed. Subsequently, the brains of these animals showed activation of an inflammatory response (increase in reactive astrocytes and interleukin1-β as well as tumor necrosis factor-α) and oxidative stress (reactive oxygen species and lipid peroxidation), causing a reduction in the number of neurons in the temporal cortex and hippocampus. Altogether, these results suggest that a HCD promotes the development of MS and contributes to the development of a neurodegenerative process and cognitive failure. In this regard, it is important to understand the relationship between MS and neuronal damage in order to prevent the onset of neurodegenerative disorders.

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Acquisition of stable arsenic tolerance in human cells following chronic arsenic exposure has not been previously reported. In the present work, we describe acquisition of stable arsenic tolerance in the human prostate epithelial cell line RWPE-1 following chronic arsenic exposure in vitro. RWPE-1 cells continuously exposed to 5 microM sodium arsenite for > or =18 weeks exhibited dramatic resistance to acute arsenite toxicity. The LC50 for acute arsenite exposure in these chronic arsenic-exposed prostate epithelial (CAsE-PE) cells was 43.8 microM versus 17.6 microM in control cells. Similar results were obtained using the antineoplastic agent arsenic trioxide. This tolerance was stable, as CAsE-PE cells grown in arsenic-free medium for 5 weeks retained their resistant phenotype. Compared to control cells, CAsE-PE cells showed a 90% reduction in arsenic accumulation over 24 h coupled with a 2.6-fold increase in the rate of arsenic efflux. CAsE-PE cells had increased basal GSH levels (4.9-fold) and increased GST activity (2.4-fold) and both GSH depletion and inhibition of GST activity abolished arsenic tolerance. Arsenic tolerance was also abolished by treatment with inhibitors of the Mdr1 and Mrp1 transporters, although no increases in mdr1 or mrp1 gene expression were observed. Our results indicate that this tolerance in human cells involves increases in GSH levels and GST activity that allow for more efficient arsenic efflux by MRP1 and MDR1. This study represents the first report of stable acquired arsenic tolerance in human cells, which could have important implications for both the toxicology and the pharmacology of arsenic.