Retinoids Inhibit Human Glioma Cell Proliferation and Migration in Primary Cell Cultures But Not in Established Cell Lines

Bouterfa, Hakim; Picht, Thomas; Keß, Daniel; Herbold, Christian; Noll, Elizabeth; Pm, Black; Roosen, K.; Jc, Tonn

doi:10.1097/00006123-200002000-00029

Cited by 81 publications

(70 citation statements)

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“…In glioma cells, cis-retinoic acid may induce differentiation and inhibit proliferation and invasiveness [14][15][16] . It may also increase the sensitivity of glioblastoma cells to conventional chemotherapy 17 .…”

Section: Discussionmentioning

confidence: 99%

Extended Adjuvant Temozolomide with cis-Retinoic Acid for Adult Glioblastoma

et al. 2012

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Objective: To determine the toxicity and effectiveness of 24 months of adjuvant temozolomide (TMZ) with cis-retinoic acid (CRA) for patients with glioblastoma. Methods: This retrospective population-based review considered the charts of all patients diagnosed with glioblastoma in Manitoba and referred to a provincial cancer centre during 2002–2008. Consecutive patients came from a population-based referral centre and provincial cancer registry. All patients were treated according to the local standard of care with surgical resection followed by concurrent radiotherapy and TMZ 75 mg/m2 daily, followed by TMZ 150–200 mg/m2 for days 1–5, repeated every 28 days for up to 24 cycles, and CRA 50 mg/m2 twice daily for days 1–21, repeated every 28 days. The main outcome measures were safety, tolerability, and effectiveness of long-term TMZ and CRA. Results: Of 247 patients diagnosed with glioblastoma in Manitoba during the study period, 116 started concurrent chemoradiotherapy, and 80 received adjuvant TMZ. Of the patients who started concurrent chemoradiotherapy, 80 began adjuvant chemotherapy. Patients completed a median of 5.5 cycles of TMZ and 3 cycles of CRA. Grade 3 or 4 hematologic toxicity was noted in 16% of patients. Median overall survival was 15.1 months, and 26.7% of patients remained alive at 2 years. Conclusions: Extended adjuvant TMZ and CRA is well tolerated. However, the population-based effectiveness of this regimen is similar to the clinical trial efficacy of 6 months of adjuvant TMZ. Future studies in glioblastoma should incorporate duration of adjuvant chemotherapy into the study design.

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Section: Discussionmentioning

confidence: 99%

Extended Adjuvant Temozolomide with cis-Retinoic Acid for Adult Glioblastoma

et al. 2012

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“…Treatment of immature astrocytes with the differentiation agent retinoic acid leads to a premature differentiation (MacFarlane and Sontheimer, 2000a) and also induces enhanced membrane expression of K ir channels. Unfortunately, retinoic acid is not able to differentiate glioma cells in culture (Bouterfa et al, 2000), and indeed, this inability to differentiate appropriately appears to be one of the important differences between glioma cells and normal astrocytes (Linskey, 1997;Schmidt et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Mislocalization of K_ir channels in malignant glia

Olsen

Sontheimer

2004

Glia

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Inwardly rectifying potassium (K ir ) channels are a prominent feature of mature, postmitotic astrocytes. These channels are believed to set the resting membrane potential near the potassium equilibrium potential (E K ) and are implicated in potassium buffering. A number of previous studies suggest that K ir channel expression is indicative of cell differentiation. We therefore set out to examine K ir channel expression in malignant glia, which are incapable of differentiation. We used two established and widely used glioma cell lines, D54MG (a WHO grade 4 glioma) and STTG-1 (a WHO grade 3 glioma), and compared them to immature and differentiated astrocytes. Both glioma cell lines were characterized by large outward K + currents, depolarized resting membrane potentials (V m )(-38.5 ± 4.2 mV, D54 and -28.1 ± 3.5 mV, STTG1), and relatively high input resistances (R m ) (260.6 ± 64.7 MΩ, D54 and 687.2 ± 160.3 MΩ, STTG1). These features were reminiscent of immature astrocytes, which also displayed large outward K + currents, had a mean V m of -51.1 ± 3.7 and a mean R m value of 627.5 ± 164 MΩ. In contrast, mature astrocytes had a significantly more negative resting membrane potential (-75.2 ± 0.56 mV), and a mean R m of 25.4 ± 7.4 MΩ. Barium (Ba 2+ ) sensitive K ir currents were >20-fold larger in mature astrocytes (4.06 ± 1.1 nS/pF) than in glioma cells (0.169 ± 0.033 nS/pF D54, 0.244 ± 0.04 nS/pF STTG1), which had current densities closer to those of dividing, immature astrocytes (0.474 ± 0.12 nS/pF). Surprisingly, Western blot analysis shows expression of several K ir channel subunits in glioma cells (K ir 2.3, 3.1, and 4.1). However, while in astrocytes these channels localize diffusely throughout the cell, in glioma cells they are found almost exclusively in either the cell nucleus (K ir 2.3 and 4.1) or ER/Golgi (3.1). These data suggest that mislocalization of K ir channel proteins to intracellular compartments is responsible for a lack of appreciable K ir currents in glioma cells.

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“…Directing these cells to a fully nonproliferative and differentiated state could improve the effectiveness of the treatments against these types of tumors. Retinoids have, in fact, a strong antitumoral effect in glioblastoma cells both in cell cultures and patients (37)(38)(39)(40), and this effect is mediated, at least in part, by promoting their expression of GFAP (38,39,41).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effect of Retinoic Acid and Cytokines on the Regulation of Glial Fibrillary Acidic Protein Expression

Herrera

Chen

Schubert

2010

Journal of Biological Chemistry

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Glial fibrillary acidic protein (GFAP) is the main astroglial marker during astrogliogenesis, but it is also expressed in other cell types, including neural stem cells and old neurons. Activation of the JAK/STAT pathway by the IL-6 family of cytokines is the canonical pathway regulating GFAP expression, whereas retinoic acid is thought to be the only inducer of GFAP to operate independently of this pathway. Here, we show that retinoic acid receptor ␣ not only links retinoic acid signaling to the canonical cytokine-stimulated pathway leading to GFAP expression but that it also plays a key role in the synergistic actions of retinoic acid and cytokines on this pathway. Cytokines both potentiate retinoic acid receptor ␣ expression and enhance its binding to DNA and to the Stat3-p300/CBP-Smad transcriptional complex, the cornerstone of the canonical pathway. PI3K is upstream to all the key events leading to the expression of GFAP. Our results give new insights about the role of retinoic acid signaling in GFAP expression.The intermediate filament protein glial fibrillary acidic protein (GFAP) 2 is considered a cell type-specific marker for astrocytes. However, GFAP is expressed in some nerve cell populations, including hippocampal neurons of older individuals (1). It is also expressed in some precursor populations of nerve cells as well as in cells that can give rise to both nerve and glia (2-4). Finally, the expression levels of GFAP within individual cells is extremely variable, and higher expression levels may limit the tumorigenicity of subpopulations of cells within glioblastomas (5, 6). Because of the wide range of cellular phenotypes associated with GFAP, it is important to understand the molecular mechanisms that regulate its expression.The GFAP is regulated in part by the secretion of factors into the extracellular space (7). The canonical pathway for GFAP expression in astrocytes is triggered by the binding of cytokines from the interleukin-6 (IL-6) family to their receptors. These receptors subsequently activate the JAK/STAT intracellular pathway, leading to the expression of GFAP in astrocytes (7-9). Most of the other pathways known to participate in GFAP expression are connected at some point to this canonical pathway (10, 11). For example, some members of the tumor growth factor-␤ (TGF-␤) superfamily of cytokines have little or no effect on GFAP synthesis by themselves, but they strongly potentiate GFAP induced by the IL-6 family of cytokines. They do so by triggering the phosphorylation, activation, and heterodimerization of Smad proteins, which then form a more potent transcriptional complex with p300/CBP and Stat3. As a consequence, the expression of GFAP is greatly enhanced (9, 12-14).All-trans-retinoic acid (RA), generally considered to be a neurogenic agent, is in fact a potent inducer of GFAP (14 -18). Studies with pharmacological agonists for the different retinoic acid receptors indicate that retinoic acid-induced GFAP expression is mediated by the activation of retinoic acid receptor (RAR) ␣ ...

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Retinoids Inhibit Human Glioma Cell Proliferation and Migration in Primary Cell Cultures But Not in Established Cell Lines

Cited by 81 publications

References 31 publications

Extended Adjuvant Temozolomide with cis-Retinoic Acid for Adult Glioblastoma

Extended Adjuvant Temozolomide with cis-Retinoic Acid for Adult Glioblastoma

Mislocalization of K_ir channels in malignant glia

Synergistic Effect of Retinoic Acid and Cytokines on the Regulation of Glial Fibrillary Acidic Protein Expression

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Retinoids Inhibit Human Glioma Cell Proliferation and Migration in Primary Cell Cultures But Not in Established Cell Lines

Cited by 81 publications

References 31 publications

Extended Adjuvant Temozolomide with cis-Retinoic Acid for Adult Glioblastoma

Extended Adjuvant Temozolomide with cis-Retinoic Acid for Adult Glioblastoma

Mislocalization of Kir channels in malignant glia

Synergistic Effect of Retinoic Acid and Cytokines on the Regulation of Glial Fibrillary Acidic Protein Expression

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Mislocalization of K_ir channels in malignant glia