Dataset Information

Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation.

ABSTRACT:

Background

The anti-epileptic drug valproic acid (VPA) has attracted attention as an anti-cancer agent.

Methods

The present study investigated effects of VPA exposure on histone deacetylase (HDAC) inhibition, cell growth, cell speed, and the degree of Erk1/2 phosphorylation in 10 cell lines (BT4C, BT4Cn, U87MG, N2a, PC12-E2, CSML0, CSML100, HeLa, L929, Swiss 3T3).

Results

VPA induced significant histone deacetylase (HDAC) inhibition in most of the cell lines, but the degree of inhibition was highly cell type-specific. Moreover, cell growth, motility and the degree of Erk1/2 phosphorylation were inhibited, activated, or unaffected by VPA in a cell type-specific manner. Importantly, no relationship was found between the effects of VPA on HDAC inhibition and changes in the degree of Erk1/2 phosphorylation, cell growth, or motility. In contrast, VPA-induced modulation of the MAPK pathway downstream of Ras but upstream of MEK (i.e., at the level of Raf) was important for changes in cell speed.

Conclusions

These results suggest that VPA can modulate the degree of Erk1/2 phosphorylation in a manner unrelated to HDAC inhibition and emphasize that changes in the degree of Erk1/2 phosphorylation are also important for the anti-cancer properties of VPA.

SUBMITTER: Gotfryd K

PROVIDER: S-EPMC2918577 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Publications

Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation.

Gotfryd Kamil K Skladchikova Galina G Lepekhin Eugene A EA Berezin Vladimir V Bock Elisabeth E Walmod Peter S PS

BMC cancer 20100721

<h4>Background</h4>The anti-epileptic drug valproic acid (VPA) has attracted attention as an anti-cancer agent.<h4>Methods</h4>The present study investigated effects of VPA exposure on histone deacetylase (HDAC) inhibition, cell growth, cell speed, and the degree of Erk1/2 phosphorylation in 10 cell lines (BT4C, BT4Cn, U87MG, N2a, PC12-E2, CSML0, CSML100, HeLa, L929, Swiss 3T3).<h4>Results</h4>VPA induced significant histone deacetylase (HDAC) inhibition in most of the cell lines, but the degree ...[more]

PMID: 20663132

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Project description:BackgroundProgressive fibrous thickening of the peritoneal membrane is a complication of long-term peritoneal dialysis (PD). TGF-β/Smad pathway activation, inflammation, and neoangiogenesis play important roles in peritoneal membrane (PM) changes induced by PD. Recently, histone deacetilase inhibitors (HDACi) have shown anti-fibrotic and anti-inflammatory effects in different experimental models. These drugs prevent deacetylation of histones causing a loosen chromatin, which in turn induce the expression of some anti-fibrotic genes. In addition, acetylation may increase the activity of proteins involved in tissue fibrosis, such as Smad7. Here, we explored the effect of valproic acid (VPA), an HDACi, on the development of peritoneal fibrosis (PF) in rats.MethodsPF was induced by daily intraperitoneal injections of 0.1% chlorhexidine gluconate (CG) for 15 consecutive days. Male Wistar rats (250-300 g) were divided into 3 groups: CONTROL, control rats receiving only vehicle; PF, peritoneal fibrosis induced in rats; PF+VPA, rats with PF treated with VPA (300 mg/kg/day by gavage). PF was assessed by Masson's trichrome staining. Inflammation and fibrosis-associated factors were assessed by immunohistochemistry, immunofluorescence, multiplex analysis, and qPCR.ResultsTreatment with VPA significantly reduced PM thickness and the expression of myofibroblasts, besides preventing loss of ultrafiltration capacity of the PM. The upregulation of profibrotic factors (TGF-β, fibronectin, and Smad3) in the PF group was significantly ameliorated by VPA. VPA modulated the TGF/Smad pathway, inhibiting phosphorylated Smad3 expression and inducing an increased Smad7 expression in the FP+VPA group. The neoangiogenesis and the expression of proinflammatory cytokines (TNF-α, IL-1β, MCP-1) observed in the PF group was significantly reduced by VPA.ConclusionsOur results indicate that VPA suppressed experimental PF through modulation of the TGF-β/Smad pathway. Interestingly, VPA treatment induced a higher expression of antifibrotic factors, such as Smad7. These results suggest that VPA may represent a potential strategy for treating long term PD complications.

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Dataset Information

Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation.

Background

Methods

Results

Conclusions

Publications

Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation.

Similar Datasets

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