Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Valproic acid (VPA), which has demonstrated efficacy in the treatment of bipolar disorder, has been shown to alter components of the phosphoinositide (PI) signaling cascade and to increase gene expression mediated by the transcription factor activator protein 1 (AP-1). Central serotonin-2A (5-HT2A) receptors, which have been implicated in the pathophysiology of manic-depressive illness, are coupled to PI hydrolysis. The promoter region of the 5-HT2A receptor gene contains AP-1 binding sites. We examined in C6 glioma cells the effect of VPA on 5-HT2A receptor signaling. Treatment of cells with VPA (100 microg/mL) for 20 h, but not 1.5 h, resulted in an enhancement of 5-HT2A receptor-stimulated PI hydrolysis. This effect of 20-h VPA exposure appeared not to be at the level of G protein or effector (i.e. phospholipase C: PLC) as inositol phosphate accumulation stimulated by aluminum fluoride or the PLC activator 2,4,6-trimethyl-N-(m-3-trifluromethylphenyl) benzenesulfonamide was not increased. The number of 5-HT2A receptors, as determined in saturation binding experiments using [3H]ketanserin, was increased by 20-h VPA treatment, with no change in affinity (KD). Taken together, our data suggest that the increase in 5-HT2A receptor-mediated PI hydrolysis following 20-h VPA exposure is not due to a general effect of VPA on this signaling cascade, but due to the up-regulation of 5-HT2A receptor number.
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PMID:Effect of valproic acid on serotonin-2A receptor signaling in C6 glioma cells. 1531 82

Valproic acid (VPA) is a potent anti-epileptic and effective mood stabilizer. It is known that VPA enhances central GABAergic activity and activates the mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) pathway. It can also inhibit various isoforms of the enzyme, histone deacetylase (HDAC), which is associated with modulation of gene transcription. Recent in vivo studies indicate a neuroprotective role for VPA, which has been found to up-regulate the expression of brain-derived neurotrophic factor (BDNF) in the rat brain. Given the interaction between the pineal hormone, melatonin, and GABAergic systems in the central nervous system, the effects of VPA on the expression of the mammalian melatonin receptor subtypes, MT1 and MT2, were examined in rat C6 glioma cells. The effects of VPA on the expression of glial cell line-derived neurotrophic factor (GDNF) and BDNF were also examined. RT-PCR studies revealed a significant induction of melatonin MT1 receptor mRNA in C6 cells following treatment with 3 or 5 mm VPA for 24 h or 5 mm VPA for 48 h. Western analysis and immunocytochemical detection confirmed that the VPA-induced increase in MT1 mRNA results in up-regulation of MT1 protein expression. Blockade of the MAPK-ERK pathway by PD98059 enhanced the effect of VPA on MT1 expression, suggesting a negative role for this pathway in MT1 receptor regulation. In addition, significant increases in BDNF, GDNF and HDAC mRNA expression were observed after treatment with VPA for 24 or 48 h. Taken together, the present findings suggest that the neuroprotective properties of VPA involve modulation of neurotrophic factors and receptors for melatonin, which is also thought to play a role in neuroprotection. Moreover, the foregoing suggests that combinations of VPA and melatonin could provide novel therapeutic strategies in neurological and psychiatric disorders.
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PMID:Novel targets for valproic acid: up-regulation of melatonin receptors and neurotrophic factors in C6 glioma cells. 1631 12

Valproic acid (VPA) has been recently investigated for its anticancer properties in different tumors, including malignant gliomas. The aim of the present work was to evaluate the effects of VPA, alone or in combination with other chemotherapeutic drugs, on in vitro growth of human glioma cell lines. A172, U373, U138, U87, and SW1783 were treated with VPA alone or in combination with mitoxantrone, etoposide, or 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU). The effects of treatments on cell growth were assessed with crystal violet staining and analyzed using the combination index (CI). The percentage of apoptotic cells and the DNA content for cell cycle phases detection were also investigated by flow cytometry. Despite a certain variability, glioma cell lines were rather resistant to the drugs tested. Addition of VPA decreased the IC50 of the chemotherapeutic agents in all cell lines tested. This effect was more evident with BCNU. The synergic effect of the association of VPA and BCNU was related to an increased block of cell cycle with accumulation in S-G2/M phases of cell cycle rather than an increased programmed cell death. In our experimental model, VPA showed anticancer properties per se on human glioma cell lines and our data support the hypothesis that, if used in association with conventional chemotherapy, it might improve the effects of single chemotherapeutic agents.
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PMID:Valproic acid increases the in vitro effects of nitrosureas on human glioma cell lines. 1819 69

C6 glioma cells were treated with clinically relevant concentrations of valproic acid (0.5 or 1.0 mM) for 1-7 days and RT-PCR used to examine expression of the melatonin MT(1) receptor and selected epigenetic modulators. Valproic acid caused significant time-dependent changes in the mRNA expression of the melatonin MT(1) receptor, histone deacetylase (HDAC) 1, 2 and 3, and methyl CpG binding protein 2 (MeCP2). A structurally distinct HDAC inhibitor, trichostatin A, also caused a significant concentration-dependent induction of melatonin MT(1) receptor mRNA expression, suggesting involvement of an epigenetic mechanism. The ability of clinical concentrations of valproic acid to significantly alter melatonin MT(1) receptor expression, suggests a role for this receptor in the diverse neuropharmacological and oncostatic effects of this agent.
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PMID:Clinically relevant concentrations of valproic acid modulate melatonin MT(1) receptor, HDAC and MeCP2 mRNA expression in C6 glioma cells. 1855 52

Replication-conditional (oncolytic) mutants of herpes simplex virus (HSV), are considered promising therapeutic alternatives for human malignancies, and chemotherapeutic adjuvants are increasingly sought to augment their efficacy. Histone deacetylase (HDAC) inhibitors are a new class of antineoplastic agents because of their potent activity in growth arrest, differentiation, and apoptotic death of cancer cells. The ability of the HDAC inhibitors to upregulate exogenous transgene expression and inhibit interferon (IFN) responses prompted our exploration of their use in improving the antitumor efficacy of oncolytic HSV. We discovered that the yield of viral progeny increased significantly when cultured glioma cells were treated with HDAC inhibitors before viral infection. Valproic acid (VPA), a commonly used antiepileptic agent with HDAC inhibitory activity, proved most effective when used to treat glioma cells before viral infection, but not concomitantly with viral infection. Pretreatment with VPA inhibited the induction of several IFN-responsive antiviral genes, augmented the transcriptional level of viral genes, and improved viral propagation, even in the presence of type I IFNs. Moreover, VPA pretreatment improved the propagation and therapeutic efficacy of oncolytic HSV in a human glioma xenograft model in vivo. These findings indicate that HDAC inhibitors can improve the efficacy of tumor virotherapies.
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PMID:Histone deacetylase inhibitors augment antitumor efficacy of herpes-based oncolytic viruses. 1864 50

Valproic acid (VPA) inhibits histone deacetylase and has been reported to induce apoptosis in glioma. We report 44 heavily pretreated pediatric patients with high-grade glioma or diffuse intrinsic pontine glioma who received VPA as oral continues maintenance treatment with individual dose adaptation. The tumor status when starting the drug was: no measurable disease in 12, measurable but stable disease in 12, and measurable progressive disease in 22 patients. Average trough blood levels of VPA were 99 mg/l. The most frequent complaint was somnolence (three patients), but no severe toxicity was reported. One relapse patient responded, early progression of disease was observed in three frontline patients and in six relapsed patients. Median overall survival duration for all patients was 1.33 years, with large differences between first-line (5-year overall survival, 44%) and relapse therapy (5-year overall survival, 14%). This shows that valproate is safe in this patient population. The moderate tumor efficacy encourages studying the drug further as an element of multi-agent protocols.
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PMID:Valproic acid was well tolerated in heavily pretreated pediatric patients with high-grade glioma. 1867 79

Valproate is an anticonvulsant drug but also a mood stabilizer commonly used to treat bipolar disorder. It has a structure of short-chain fatty acid and is becoming a first line treatment for bipolar disorder. The effect mechanism of the vaproate has not been completely established but it has been suggested that alterations in gene expression may be involved in chronic treatment. On the other hand, a growing body of evidence emphasizes that valproate has neuroprotective and neurotrophic actions. Neuroimaging studies that examine neurochemistry in the living brain provide further support for the hypothesis that bipolar disorder is related to changes in neuronal viability and function. In cellular view of point, it was showed that valproate protected rat cerebral cortical and cerebellar granule cells from glutamate-related excitotoxicity, and apoptotic death of the endoplasmic reticulum in C6 glioma cells and PC 12 cells. At the genetic level, growing data suggest that the long-term treatment of mood disorders may involve the regulation of signalling pathways and gene expression in critical neuronal circuits. It has been shown that lithium and valproate produce some changes in basal and stimulated DNA binding to activator protein 1 (AP-1) transcription factors, considering that strategic changes in gene expression in critical neuronal circuits may be important in the treatment of a variety of psychiatric disorders. So, a growing body of evidence establishes its neuroprotective and neurotrophic actions in bipolar disorder.
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PMID:Valproate and neuroprotective effects for bipolar disorder. 2037 54

Temozolomide (TMZ) has become a key therapeutic agent in patients with malignant gliomas; however, its survival benefit remains unsatisfactory. Valproic acid (VPA) has emerged as an anticancer drug via inhibition of histone deacetylases (HDACs), but the therapeutic advantages of a combination with VPA and TMZ remain poorly understood. The main aim of the present study was to determine whether an antitumor effect could be potentiated by a combination of VPA and TMZ, especially in TMZ-resistant cell lines. A combination of VPA and TMZ had a significantly enhanced antitumor effect in TMZ-resistant malignant glioma cells (T98 and U138). This enhanced antitumor effect correlated with VPA-mediated reduced O6-methylguanine-DNA methyltransferase (MGMT) expression, which plays an important role in cellular resistance to alkylating agents. In vitro, the combination of these drugs enhanced the apoptotic and autophagic cell death, as well as suppressed the migratory activities in TMZ-resistant cell lines. Furthermore, in vivo efficacy experiment showed that treatment of combination of VPA and TMZ significantly inhibited tumor growth compared with the monotherapy groups of mice. These results suggest that the clinical efficacy of TMZ chemotherapy in TMZ-resistant malignant glioma may be improved by combination with VPA.
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PMID:Valproic acid downregulates the expression of MGMT and sensitizes temozolomide-resistant glioma cells. 2270 11

Valproic acid (VPA), an histone deacetylase inhibitor, is emerging as a promising therapeutic agent for the treatments of gliomas by virtue of its ability to reactivate the expression of epigenetically silenced genes. VPA induces the unfolded protein response (UPR), an adaptive pathway displaying a dichotomic yin yang characteristic; it initially contributes in safeguarding the malignant cell survival, whereas long-lasting activation favors a proapoptotic response. By triggering UPR, VPA might tip the balance between cellular adaptation and programmed cell death via the deregulation of protein homeostasis and induction of proteotoxicity. Here we aimed to investigate the impact of proteostasis on glioma stem cells (GSC) using VPA treatment combined with subversion of SEL1L, a crucial protein involved in homeostatic pathways, cancer aggressiveness, and stem cell state maintenance. We investigated the global expression of GSC lines untreated and treated with VPA, SEL1L interference, and GSC line response to VPA treatment by analyzing cell viability via MTT assay, neurosphere formation, and endoplasmic reticulum stress/UPR-responsive proteins. Moreover, SEL1L immunohistochemistry was performed on primary glial tumors. The results show that (i) VPA affects GSC lines viability and anchorage-dependent growth by inducing differentiative programs and cell cycle progression, (ii) SEL1L down-modulation synergy enhances VPA cytotoxic effects by influencing GSCs proliferation and self-renewal properties, and (iii) SEL1L expression is indicative of glioma proliferation rate, malignancy, and endoplasmic reticulum stress statuses. Targeting the proteostasis network in association to VPA treatment may provide an alternative approach to deplete GSC and improve glioma treatments.
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PMID:Down-modulation of SEL1L, an unfolded protein response and endoplasmic reticulum-associated degradation protein, sensitizes glioma stem cells to the cytotoxic effect of valproic acid. 2431 81

Valproic acid (VPA) is a well-tolerated drug that is used to treat seizure disorders and that has recently been shown to inhibit histone deacetylase. The present study investigated the effects of VPA on the radiosensitization of the rat C6 glioma cell line in vitro. To select an appropriate treatment concentration and time, MTT and flow cytometry assays were performed to measure the inhibitory effects of VPA at various concentrations and incubation time-points. The radiosensitizing effect of VPA was determined using clonogenic experiments. VPA- and radiation-induced C6 apoptosis was analyzed using quantitative polymerase chain reaction and western blot analysis. Cell proliferation was significantly inhibited by VPA in a time- and dose-dependent manner (P<0.05). VPA enhanced radiation-induced C6 cell death and there was clear inhibition of clonogenic formation [sensitizer enhancement ratio (SER), 1.30]. This effect was closely associated with the concentration of VPA. VPA treatment decreased the mRNA and protein levels of Bcl-2, whereas increased changes were detected with Bax. At a concentration of 0.5 mmol/l, VPA had a low toxicity and enhanced the radiosensitization of the C6 cells. VPA may radiosensitize glioma cells by inhibiting cellular proliferation and inducing apoptosis by regulating apoptosis-related molecular changes.
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PMID:Histone deacetylase inhibitor, valproic acid, radiosensitizes the C6 glioma cell line in vitro. 2434 49


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