Valproic acid and interferon-α synergistically inhibit neuroblastoma cell growth in vitro and in vivo

Michaelis, Martin; Suhan, Tatyana; Činátl, Jaroslav; Driever, Pablo Hernáiz; Činátl, Jindřich

doi:10.3892/ijo.25.6.1795

Cited by 33 publications

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“…37 The assay is based on simultaneous detection of incorporated bromodeoxyuridine in the DNA of dividing cells and the determination of the amount of cellular DNA by staining with 7-aminoactinomycin. This combination allows to characterise cells that actively synthesise DNA depending on their position in the cell cycle (i.e.…”

Section: Cell Cycle Analysismentioning

confidence: 99%

“…Apoptotic cells were detected as described previously 37 using a commercial kit (R&D Systems, Wiesbaden, Germany) following the manufacturer's instructions by flow cytometry (FacsCalibur, BD Biosciences, Heidelberg, Germany). The assay is based on the detection of apoptotic cells using fluoresceinisothiocyanate-conjugated annexin V. Phosphatidylserine is exposed on the outer leaflet of the cytoplasm membrane early during apoptosis.…”

Section: Apoptosis Assaymentioning

confidence: 99%

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Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells

et al. 2005

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The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was recently shown to inhibit angiogenesis, but displays no toxicity in endothelial cells. Here, we demonstrate that VPA increases extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation in human umbilical vein endothelial cells (HUVEC). The investigation of structurally modified VPA derivatives revealed that the induction of ERK 1/2 phosphorylation is not correlated to HDAC inhibition. PD98059, a pharmacological inhibitor of the mitogenactivated protein kinase kinase 1/2, prevented the VPAinduced ERK 1/2 phosphorylation. In endothelial cells, ERK 1/2 phosphorylation is known to promote cell survival and angiogenesis. Our results showed that VPA-induced ERK 1/2 phosphorylation in turn causes phosphorylation of the antiapoptotic protein Bcl-2 and inhibits serum starvationinduced HUVEC apoptosis and cytochrome c release from the mitochondria. Moreover, the combination of VPA with PD98059 synergistically inhibited angiogenesis in vitro and in vivo.

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Section: Cell Cycle Analysismentioning

confidence: 99%

Section: Apoptosis Assaymentioning

confidence: 99%

Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells

et al. 2005

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“…10,11 As recently demonstrated it shows antiangiogenetic effects and inhibits HDAC. 12,13 Limited studies analyzed the effects of HDI on cell lines derived from embryonal tumors of the nervous systemmostly neuroblastomas (NB). Michaelis et al found increased acetylation of histones in neuroblastoma cell lines treated with VPA.…”

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confidence: 99%

“…Michaelis et al found increased acetylation of histones in neuroblastoma cell lines treated with VPA. 12 Jaboin et al used MS-275 in the treatment of cell lines, derived from a number of childhood solid tumors, including neuroblastoma (SMS-KCN), medulloblastoma (Daoy) and renal rhabdoid (G401).…”

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confidence: 99%

Inhibitors of histone deacetylases as potential therapeutic tools for high‐risk embryonal tumors of the nervous system of childhood

Furchert

Lanvers-Kaminsky

Juürgens

et al. 2007

Intl Journal of Cancer

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The origin of malignant embryonal tumors is incompletely understood and certain risk groups remain difficult to treat. The epigenetic structure of DNA and its lesions play a role in the origin of these neoplasms. Manipulation of the epigenome may offer novel treatment options. The authors evaluated the cytotoxicity of histone deacetylase inhibitors (HDI) [MS-275, SAHA, TSA, M344, M360, D85, SW55, SW187 and valproic acid (VPA)] on 13 embryonal tumor cell lines [4 medulloblastomas, 5 neuroblastomas, 2 atypical teratoid/rhabdoid tumors (AT/RT), and 2 malignant rhabdoid tumors of the kidney (RTK)] in MTT assay. In addition, HDI effects on hyperacetylation, reexpression of growth regulatory genes and apoptosis were characterized by Western analysis, RT-PCR and annexin-V staining. All HDI inhibited cell proliferation in a time-and dose-dependent manner. VPA was least cytotoxic with GI 50 values after 72 hr ranging from 53.6 to 332.9 lM, while TSA was most efficient with GI 50 values after 72 hr ranging from 0.01 to 8.8 lM. M344 and M360 were also highly effective. Western blot revealed hyperacetylation of histone H4 after HDI treatment. Reactivation of several genes including the proapoptotic CASP8 was identified by RT-PCR. Annexin-V staining demonstrated a dose and time dependent induction of apoptosis. HDI inhibited the growth of medulloblastoma, neuroblastoma and rhabdoid tumors in vitro. Treatment with HDI induced the reactivation of growth regulatory genes and consequently apoptosis. Our results warrant further studies and may help in the design of new protocols geared at the treatment of high risk embryonal tumors. ' 2007 Wiley-Liss, Inc.

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“…The LDH was quantified using the CytoTOX-ONE TM Assay from Promega UK Ltd. The MTT assay was adapted (3) . eNOS phosphorylation and eNOS concentration were analysed by Westernblotting techniques with the appropriate antibody.…”

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confidence: 99%

Mechanisms underlying the impact of long-chain n-3 PUFA on vascular reactivity

2008

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CVD is the leading cause of death in the world. About eighteen million individuals worldwide die from the disease annually. Mortality rates vary considerably between countries; rates are lower in Japan and Mediterranean countries and highest in Eastern Europe (1) . Vascular function and reactivity is emerging as an important CVD risk factor and there is accumulating evidence to suggest that the amount and composition of fat in the diet is a major factor influencing endothelial cell function and vascular tone. Many studies have shown that dietary n-3 PUFA may have beneficial effects on vascular reactivity (2) . The endothelial NO synthase (eNOS) enzyme plays an important role in the regulation of vascular function, as it produces NO, which is an important vasodilator. However, the impact of longchain n-3 PUFA on eNOS activity remains poorly understood. The aim of the present in vitro study was to determine the impact of the long-chain n-3 PUFA EPA, docosapentaenoic acid (DPA) and DHA on NO production and eNOS regulatory pathways in human umbilical vein endothelial cells (HUVEC).HUVEC (70-90 % confluence) were incubated for 30 min, 4 h and 24 h with the individual fatty acids in BSA complex solution (2.5 :1, v/v) at 0-100 mM. Cytotoxicity effects were measured by Lactate Dehydrogenase (LDH) assay and MTT assay. The LDH was quantified using the CytoTOX-ONE TM Assay from Promega UK Ltd. The MTT assay was adapted (3) . eNOS phosphorylation and eNOS concentration were analysed by Westernblotting techniques with the appropriate antibody. All experiments were repeated at least in triplicate.There was no significant toxic effect of any of fatty acid concentration in either the LDH assay or the MTT assay. The present study demonstrated that fish oil fatty acids (DHA, EPA and DPA) and Palmitic acid (0-100 mM for 30 min, 4 and 24 h) influenced eNOS phosphorylation and eNOS protein level in HUVEC. There was no significant effect on the ratio of eNOS phosphorylation and eNOS concentration for most of the fatty acids except with the 24 hr incubation time at 0, 1, 10 and 100 mM DHA (P £ 0.04) and with the 4 hr incubation at 25 and 100 mM PA (P£0.01). There was a trend toward increased eNOS phosphorylation to concentration ratio at 4 hrs in response to EPA with a dose effect evident but this did not reach significance (P > 0.05) (Figure 1). This result indicated that an increase in eNOS phosphorylation and eNOS protein level with EPA treatment may positively induce eNOS activity and NO production. In conclusion, there was little evidence of an effect of EPA, DPA or DHA on eNOS phosphorylation status in HUVEC cells, with evidence of a decrease following 24 h of exposure to DHA.

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Valproic acid and interferon-α synergistically inhibit neuroblastoma cell growth in vitro and in vivo

Cited by 33 publications

References 0 publications

Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells

Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells

Inhibitors of histone deacetylases as potential therapeutic tools for high‐risk embryonal tumors of the nervous system of childhood

Mechanisms underlying the impact of long-chain n-3 PUFA on vascular reactivity

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