Effect of trichostatin A, a histone deacetylase inhibitor, on glioma proliferation in vitro by inducing cell cycle arrest and apoptosis

Wetzel, Matthew; Premkumar, Daniel R.; Arnold, Beth; Pollack, Ian F.

doi:10.3171/ped.2005.103.6.0549

Cited by 32 publications

(51 citation statements)

References 30 publications

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“…TSA treatment caused significant cell death at 48 h, and no cell damage was found in 5-Aza-dC treated cells. Similar results were reported previously in the treatment of cancer cells with epigenetic reagents (28,29).…”

Section: Heparanase Expression Is Restored By Epigenetic Modificationssupporting

confidence: 80%

Heparanase expression is associated with histone modifications in glioblastoma

et al. 2011

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Abstract. In this study we investigated epigenetic modifications such as DNA methylation, histone acetylation and histone methylation in the regulation of heparanase expression in glioblastoma. We found that heparanase promoters are differentially methylated among three glioblastoma cell lines; however, all these cells expressed baseline levels of heparanase. 5-Aza-2'-deoxycytidine (5-Aza-dC), a DNA methyltransferase inhibitor, revoked heparanase expression in all the examined cells. Trichostatin A (TSA), a histone deacetylase inhibitor, activated heparanase expression in promoter unmethylated LN229 and T98G cells but not in promoter methylated U251n cells. To identify the mechanisms of heparanase induction by 5-Aza-dC, heparanase expression-related transcription factors were examined. No detected transcription factors (EGR1, Ets1, GABPα and Sp1) were found to be induced either by 5-Aza-dC or TSA. Furthermore, we found that 5-Aza-dC increased acetylation of histone H3 and di-methylation of histone H3 lysine K4 (H3K4me2) in LN229 and T98G cells. The increased histone acetylation and H3K4me2 were also observed in heparanaseexpressing tumor tissues by immunohistochemistry staining. Additionally, we found that nuclear factor κB (NFκB) p65 but not NFκB p50 was correlated with heparanase expression, which could be expressed both by neoplastic cells and angiogenesis-related neovessel cells. However, we did not observe any regulatory mechanism between heparanase and NFκB p65 via transient transfection of their cDNA in T98G and U251n cells. We concluded that heparanase expression is associated with histone modifications and promoter DNA methylation plays a role in the control of gene silencing. Overexpression of both heparanase and NFκB p65 may be the result of excessive histone modifications.

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Section: Heparanase Expression Is Restored By Epigenetic Modificationssupporting

confidence: 80%

Heparanase expression is associated with histone modifications in glioblastoma

et al. 2011

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“…5B). Because the CDK inhibitor p21WAF1 was increased in glioma cells by TSA (Wetzel et al, 2005), we tested the time course of SAHAmediated p21 expression. Cells were exposed to varying concentrations of SAHA; lysates were prepared and probed with antibodies recognizing p21 Cip/Waf.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Cip/Waf expression and decreased phosphorylated retinoblastoma protein (Wetzel et al, 2005). Suberoylanalide hydroxamic acid (SAHA, vorinostat), an inhibitor of several members of the HDAC protein family (Finnin et al, 1999), has also been observed to have antiglioma activity in preclinical studies, causing GBM cells to accumulate in the G 2 -M phase of the cell cycle, with increased expression of p21WAF1 and p27KIP1, decreased levels of cyclin-dependent kinase (CDK) 2, CDK4, cyclin D1, and cyclin D2 (Yin et al, 2007), and inhibition of GBM growth in orthotopic models.…”

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confidence: 99%

Abrogation of Mitogen-Activated Protein Kinase and Akt Signaling by Vandetanib Synergistically Potentiates Histone Deacetylase Inhibitor-Induced Apoptosis in Human Glioma Cells

Jane¹,

Premkumar²,

Addo-Yobo³

et al. 2009

J Pharmacol Exp Ther

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Vandetanib is a multitargeted tyrosine kinase inhibitor. Our initial studies demonstrated that this agent blocks vascular endothelial growth factor receptor, epidermal growth factor receptor, and platelet-derived growth factor receptor phosphorylation and mitogen-activated protein kinase (MAPK)-mediated signaling in glioma cell lines in a dose-dependent manner. Despite these effects, we observed that vandetanib had little effect on apoptosis induction at clinically achievable concentrations. Because histone deacetylase inhibitors (HDACIs) have been suggested to regulate signaling protein transcription and downstream interactions via modulation of protein chaperone function through the 90-kDa heat shock protein, we investigated whether combining vandetanib with an HDACI could synergistically potentiate signaling pathway inhibition and apoptosis induction in a panel of malignant human glioma cell lines. Proliferation assays, apoptosis induction studies, and Western immunoblot analysis were conducted in cells treated with vandetanib and HDACIs as single agents or in combination. Vandetanib and suberoylanalide hydroxamic acid reduced proliferation in all cell lines when used as single agents, and the combination produced marked potentiation of growth inhibition as assessed by combinatorial methods. These effects were paralleled by potentiation of Akt signaling inhibition and apoptosis induction. Our results indicate that inhibition of histone deacetylation enhances the antiproliferative effect of vandetanib in malignant human glioma cell lines by enhancing inhibition of MAPK, Akt, and other downstream effectors that may have application in combinatorial therapeutics for these tumors.

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“…A ação da tricostatina A foi testada in vitro em vários tipos de células tumorais, demonstrando seu efeito inibitório no ciclo celular e apoptose (MEDINA et al, 1997;VIGUSHIN et al, 2001;YEE et al, 2004;WETZEL et al, 2005;MUKHOPADHYAY et al, 2006) e invasão celular (WU; STARZINSKI-POWITZ;…”

Section: Zinco-independentes Nicotinamida-adenina Dinucleotídeo Depeunclassified

“…Quando associado a 5-aza-2-deoxicitidina (AZA) (CANTOR et al, 2007), ácido retinóico (TOUMA et al, 2005) HENDERSON et al, 2003;WETZEL et al, 2005;MUKHOPADHYAY et al, 2006;STARZINSKI-POWITZ;HONG et al, 2009 aumento na fração sub-G1 do ciclo celular. Interessantemente, o tratamento com 1000 µg/ml de RBPP nas células produziu um aumento na proporção de células marcadas na fase S dos tempos de 48 e 72h, e diminuição concomitante na proporção de células em G1 e G2.…”

Section: Estudosunclassified

Estabelecimento e caracterização de modelo xenotransplantável de mastocitoma canino para estudo de antineoplásicos

Nagamine¹

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A meus pais, pela dedicação incondicional em nossa formação moral e no incentivo aos estudos À minha tia Haruko, minha segunda mãe, por sua inquestionável generosidade, sem a qual não teria feito trabalho nenhumEm especial à Ana Carolina Caldas Alves, minha terapeuta, que conseguiu abrir uma portinha que eu havia fechado. Foi seu trabalho que se transformou neste. Minha sincera gratidão. AGRADECIMENTOS

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Effect of trichostatin A, a histone deacetylase inhibitor, on glioma proliferation in vitro by inducing cell cycle arrest and apoptosis

Cited by 32 publications

References 30 publications

Heparanase expression is associated with histone modifications in glioblastoma

Heparanase expression is associated with histone modifications in glioblastoma

Abrogation of Mitogen-Activated Protein Kinase and Akt Signaling by Vandetanib Synergistically Potentiates Histone Deacetylase Inhibitor-Induced Apoptosis in Human Glioma Cells

Estabelecimento e caracterização de modelo xenotransplantável de mastocitoma canino para estudo de antineoplásicos

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