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Molecular and therapeutic potential and toxicity of valproic acid.

Chateauvieux S, Morceau F, Dicato M, Diederich M - J. Biomed. Biotechnol. (2010)

Bottom Line: Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer.Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels.VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Fondation de Recherche Cancer et Sang, Hôpital Kirchberg, Kirchberg 2540, Luxembourg.

ABSTRACT
Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels. VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. VPA is a widely used drug, particularly for children suffering from epilepsy. Due to the increasing number of clinical trials involving VPA, and interesting results obtained, this molecule will be implicated in an increasing number of therapies. However side effects of VPA are substantially described in the literature whereas they are poorly discussed in articles focusing on its therapeutic use. This paper aims to give an overview of the different clinical-trials involving VPA and its side effects encountered during treatment as well as its molecular properties.

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Related in: MedlinePlus

Pharmacological activity of VPA described in the literature. Schematic representation of direct and indirect targets of VPA. Principal direct targets known for VPA are ionic channels and ABAT (in green). Epigenetic action of VPA (in violet) as HDACi activity: VPA targets the transcriptomic system and principally directly inhibits HDAC class I (subcategories 1, 2, and 3), and less strongly class II/a (subcategories 4, 5, and 7), but induces HDAC 9 and 11, and indirectly inhibits the function of SMC and DNMT. Probably due to its epigenetic properties, or interactions not yet established, VPA alters, directly or indirectly, expression of many molecules involved in molecular pathways such as apoptosis, inflammation, differentiation, and proliferation (in red).
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fig2: Pharmacological activity of VPA described in the literature. Schematic representation of direct and indirect targets of VPA. Principal direct targets known for VPA are ionic channels and ABAT (in green). Epigenetic action of VPA (in violet) as HDACi activity: VPA targets the transcriptomic system and principally directly inhibits HDAC class I (subcategories 1, 2, and 3), and less strongly class II/a (subcategories 4, 5, and 7), but induces HDAC 9 and 11, and indirectly inhibits the function of SMC and DNMT. Probably due to its epigenetic properties, or interactions not yet established, VPA alters, directly or indirectly, expression of many molecules involved in molecular pathways such as apoptosis, inflammation, differentiation, and proliferation (in red).

Mentions: Epigenetic processes, such as histone deacetylation and DNA methylation, are known to contribute to the cancerous transformation of cells by silencing critical genes, leading to chemotherapy resistance. It has been hypothesized that HDACi act through a derepression or a stimulation of silenced tumor suppressor genes [46–48]. Several data demonstrate the ability of these epigenetic drugs to modulate global gene expression in tumors (Figure 2).


Molecular and therapeutic potential and toxicity of valproic acid.

Chateauvieux S, Morceau F, Dicato M, Diederich M - J. Biomed. Biotechnol. (2010)

Pharmacological activity of VPA described in the literature. Schematic representation of direct and indirect targets of VPA. Principal direct targets known for VPA are ionic channels and ABAT (in green). Epigenetic action of VPA (in violet) as HDACi activity: VPA targets the transcriptomic system and principally directly inhibits HDAC class I (subcategories 1, 2, and 3), and less strongly class II/a (subcategories 4, 5, and 7), but induces HDAC 9 and 11, and indirectly inhibits the function of SMC and DNMT. Probably due to its epigenetic properties, or interactions not yet established, VPA alters, directly or indirectly, expression of many molecules involved in molecular pathways such as apoptosis, inflammation, differentiation, and proliferation (in red).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2926634&req=5

fig2: Pharmacological activity of VPA described in the literature. Schematic representation of direct and indirect targets of VPA. Principal direct targets known for VPA are ionic channels and ABAT (in green). Epigenetic action of VPA (in violet) as HDACi activity: VPA targets the transcriptomic system and principally directly inhibits HDAC class I (subcategories 1, 2, and 3), and less strongly class II/a (subcategories 4, 5, and 7), but induces HDAC 9 and 11, and indirectly inhibits the function of SMC and DNMT. Probably due to its epigenetic properties, or interactions not yet established, VPA alters, directly or indirectly, expression of many molecules involved in molecular pathways such as apoptosis, inflammation, differentiation, and proliferation (in red).
Mentions: Epigenetic processes, such as histone deacetylation and DNA methylation, are known to contribute to the cancerous transformation of cells by silencing critical genes, leading to chemotherapy resistance. It has been hypothesized that HDACi act through a derepression or a stimulation of silenced tumor suppressor genes [46–48]. Several data demonstrate the ability of these epigenetic drugs to modulate global gene expression in tumors (Figure 2).

Bottom Line: Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer.Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels.VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Fondation de Recherche Cancer et Sang, Hôpital Kirchberg, Kirchberg 2540, Luxembourg.

ABSTRACT
Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels. VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. VPA is a widely used drug, particularly for children suffering from epilepsy. Due to the increasing number of clinical trials involving VPA, and interesting results obtained, this molecule will be implicated in an increasing number of therapies. However side effects of VPA are substantially described in the literature whereas they are poorly discussed in articles focusing on its therapeutic use. This paper aims to give an overview of the different clinical-trials involving VPA and its side effects encountered during treatment as well as its molecular properties.

Show MeSH
Related in: MedlinePlus