Interferon Gamma Inhibits Proliferation and Hyaluronic Acid Adhesion of Human Malignant Glioma Cells in Vitro

Knüpfer, M.; Knüpfer, Heike; Gool, Stefaan Van; Domula, M; Wolff, Johannes

doi:10.1006/cyto.1999.0575

Cited by 35 publications

(30 citation statements)

References 10 publications

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“…Furthermore, the expression of proteins involved in the maintenance of heterochromatin, such as the SMC proteins, SMC-associated proteins, DNMT1, and HP1, affects the dynamics of the chromatin structure. As reported in other cell systems (18)(19)(20)(21)(22)(23)(28)(29)(30), we observed a rapid, but reversible, histone hyperacetylation in the examined breast cancer cells and the MCF-7 xenograft model with clinically relevant concentrations of VPA. In the cultured cells, the maximal effects occurred by 1 hour of exposure (Fig.…”

Section: Discussionsupporting

confidence: 87%

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Valproic Acid Alters Chromatin Structure by Regulation of Chromatin Modulation Proteins

et al. 2005

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Histone acetylation and deacetylation are crucial in the regulation of gene expression. Dynamic changes in gene expression may affect chromatin structure and, consequently, the interaction of chromatin with regulatory factors. In this study, the effects of the antiseizure drug valproic acid (VPA) on the expression of genes that regulate the structure of chromatin and the access of macromolecules to the DNA were investigated. Exposure of breast cancer cells to VPA resulted in rapid dose-dependent hyperacetylation of the histones H3 and H4. VPA further induced a depletion of several members of the structural maintenance of chromatin (SMC) proteins, SMC-associated proteins, DNA methyltransferase, and heterochromatin proteins. Down-regulation of these proteins was associated with chromatin decondensation. The observed alterations of chromatin structure correlated with enhanced sensitivity of DNA to nucleases and increased interaction of DNA with intercalating agents. VPA-induced chromatin decondensation led to a sequence-specific potentiation of DNA-damaging agents in cell culture and xenograft models. Modulation of heterochromatin maintenance proteins was not a direct, but a downstream, effect of histone acetylation. The effects on the chromatin structure were reversible upon drug withdrawal, but obligatory for the potentiation of DNA-damaging agents. In addition to their antitumor activity as single agents, the chromatin decondensation induced by histone deacetylase inhibitors may enhance the efficacy of cytotoxic agents that act by targeting DNA. The proposed mechanism of action suggests an effect of drug sequencing on the antitumor activity of these drugs. (Cancer Res 2005; 65(9): 3815-22)

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Section: Discussionsupporting

confidence: 87%

“…Several studies have suggested that treatment of cells with VPA results in histone hyperacetylation, growth arrest, and cell differentiation in several tumor cell lines (18)(19)(20)(21)(22)(23). We found that VPA induced maximal histone H4 acetylation as early as 1 hour (Fig.…”

Section: Resultssupporting

confidence: 53%

Valproic Acid Alters Chromatin Structure by Regulation of Chromatin Modulation Proteins

et al. 2005

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“…The epirubicin dose selected for the presented experiments was based on prior studies suggesting a feasibility of this dose when given weekly for at least 3 weeks; higher concentrations resulted in delayed deaths. 1 Higher concentrations were feasible when given as a single injection.…”

Section: Cell Linesmentioning

confidence: 99%

In vivo synergy between topoisomerase II and histone deacetylase inhibitors: predictive correlates

Marchion

Biçaku

Daud

et al. 2005

Molecular Cancer Therapeutics

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Histone deacetylase inhibitors (HDACi) are a promising class of anticancer agents, yet the specific biological effects resulting in cell death are still poorly understood and clinically relevant markers of response are not adequately defined. The anticonvulsant valproic acid has recently emerged as an HDACi, and in vitro studies suggested that valproic acid may potentiate cytotoxic agents. We evaluated the pharmacologic and biological effects of valproic acid on histone acetylation, chromatin structure, and DNA damage induced by topoisomerase II inhibitors in mice bearing breast cancer tumors and developed an ex vivo methodology for response prediction using comet assays. The exposure of mice to valproic acid before exposure to epirubicin led to tumor regression when valproic acid was given for 48 hours at concentrations sufficient for histone hyperacetylation, down-regulation of heterochromatin maintenance proteins, and chromatin decondensation. Tumor response was accurately predicted by ex vivo comet moments. Valproic acid did not exacerbate epirubicin-related toxicity. Antitumor effects were not observed with valproic acid alone despite biologically active valproic acid concentrations. These findings suggest that exposure of tumor-bearing mice to valproic acid potentiated the antitumor effects of topoisomerase II inhibitors without enhancing toxicity. The HDACi-induced histone acetylation and modulation of heterochromatin correlated with potentiation of epirubicinmediated DNA damage. However, these effects did not result in antitumor activity when using a HDACi alone and hence should not be considered a surrogate marker. Ex vivo comet assays may be useful as a predictive tool when tumor cells are limited and serial biopsies are difficult to obtain.

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“…The cells were harvested and the 3 H activity was quantitated. Cell survival is directly related to radioactive incorporation value (26).…”

Section: [ 3 H]thymidine Incorporationmentioning

confidence: 99%

Tumor Necrosis Factor-α Differentially Modulates CD44 Expression in Ovarian Cancer Cells

Muthukumaran

Miletti-González

Ravindranath

et al. 2006

Molecular Cancer Research

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Chronic inflammation is implicated in the pathophysiology of ovarian cancer. Tumor necrosis factor-A (TNF-A), a major inflammatory cytokine, is abundant in the ovarian cancer microenvironment. TNF-A modulates the expression of CD44 in normal T lymphocytes and CD44 is implicated in ovarian carcinogenesis and metastases. However, little is known about the role of TNF-A in CD44 expression of cancer cells. Recent clinical work using TNF-A inhibitors for the treatment of ovarian cancer makes the study of TNF-A interactions with CD44 crucial to determining treatment a success or a failure. We studied the effect of TNF-A on ovarian cancer cells viability, CD44 expression, and in vitro migration/invasion. Our results revealed that TNF-A differentially modulates the expression of CD44 in TNF-A-resistant ovarian cancer cells, affecting their in vitro migration, invasion, and binding to hyaluronic acid. TNF-A up-regulation of CD44 expression was dependent on the activation of c-Jun NH 2 -terminal kinase (JNK) and this activation was accompanied by an increase in their invasive phenotype. On the contrary, if TNF-A failed to induce JNK phosphorylation, the end result was down-regulation of both CD44 expression and the invasive phenotype. These results were confirmed by the use of JNK inhibitors and a TNF receptor competitive inhibitor.

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Interferon Gamma Inhibits Proliferation and Hyaluronic Acid Adhesion of Human Malignant Glioma Cells in Vitro

Cited by 35 publications

References 10 publications

Valproic Acid Alters Chromatin Structure by Regulation of Chromatin Modulation Proteins

Valproic Acid Alters Chromatin Structure by Regulation of Chromatin Modulation Proteins

In vivo synergy between topoisomerase II and histone deacetylase inhibitors: predictive correlates

Tumor Necrosis Factor-α Differentially Modulates CD44 Expression in Ovarian Cancer Cells

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