Valproic acid affected the survival and invasiveness of human glioma cells through diverse mechanisms.
ABSTRACT The effects of valproic acid (VPA) on the viability, apoptosis, and invasiveness of two glioma cells (A172 and T98G) and the underlying mechanisms were studied. VPA induced cytotoxicity and apoptosis, and suppressed the invasiveness of both cells. VPA increased the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 in A172 cells, but decreased it in T98G cells. siRNA blockade of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression partially reversed VPA-mediated effects in T98G cells, but had no effect on A172 cells. VPA increased the expression of phospho-JNK1 and phospho-ERK1/2 in A172 cells, but decreased it in T98G cells. Inhibition of JNK1 and/or ERK1/2 partially reversed the VPA effects in A172 cells. In conclusion, the effects of VPA (loss of viability, increased apoptosis, and decreased invasiveness) are, at least partly, mediated through the RECK-MMPs pathway in T98G cells and the mitogen-activated protein kinase pathways in A172 cells. The action of VPA seems to be cell type-specific in glioma cells.
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ABSTRACT: Matrix metalloproteinase 9 (MMP-9) is one of the most studied enzymes in cancer. MMP-9 can cleave proteins of the extracellular matrix and a large number of receptors and growth factors. Accordingly, its expression must be tightly regulated to avoid excessive enzymatic activity, which is associated with disease progression. Although we know that epigenetic mechanisms play a central role in controlling mmp-9 gene expression, predicting how epigenetic drugs could be used to suppress mmp-9 gene expression is not trivial because epigenetic drugs also regulate the expression of key proteins that can tip the balance towards activation or suppression of MMP-9. Here, we review how our understanding of the biology and expression of MMP-9 could be exploited to augment clinical benefits, most notably in terms of the prevention and management of degenerative diseases and cancer.Cellular and Molecular Life Sciences CMLS 11/2012; 70(17). DOI:10.1007/s00018-012-1214-z · 5.86 Impact Factor
- Journal of Neuro-Oncology 04/2013; 113(3). DOI:10.1007/s11060-013-1129-z · 2.79 Impact Factor
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ABSTRACT: Diffuse intrinsic pontine glioma is a pediatric oncologic disease with dismal prognosis and no effective treatment. Since 2007, our patients have been using valproic acid as prophylactic anticonvulsant. We have undertaken a retrospective study in order to evaluate the influence of valproate in the outcomes of children with this disease in our center. Patients were treated with weekly carboplatin and vincristine and received conformal radiotherapy, either concurrent or sequential. Event-free survival and overall survival of patients not treated with valproic acid were 6.5 and 7.8 months. Accelerated failure time model (a parametric multivariate regression test for time-to-failure data) showed a statistically significant superiority of the median event-free survival of treated patients (6.5 vs. 9.5 months in treated patients; HR 0.54-95 % CI 0.33-0.87; p < 0.05) and also of overall survival (7.8 vs. 13.4 months in treated patients; HR 0.60-95 % CI 0.37-0.98; p = 0.05).Journal of Neuro-Oncology 11/2013; 116(2). DOI:10.1007/s11060-013-1280-6 · 2.79 Impact Factor