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And limit the use of steroids.
"People with brain tumors should not take antidepressants or other medications or use supplements that increase serotonin." --Schor

Antidepressants increase serotonin which increases GDNF
Glial cell line-derived neurotrophic factor (GDNF)
small protein made by glial cells
aids in the survival of neurons and supports growth of tumor cells esp gliomas
helps cancerous glia migrate and invade surrounding tissue

2007 paper: amitriptyline, a tricyclic antidepressant does this
Comipramine mb an exception because it triggers apoptosis in glioma cells

other drugs of concern: steroids; prednisone, dexamethasone, et al
usually prescribed to limit brain swelling
minimize dose and use of these drugs
use high dose curcumin and boswellia to lower inflam and reduce need
dexamethasone inhibits apoptosis of glioma
2006 paper from Ireland supports this warning
steroids stop the chemo drug camptothecin from killing glioma cells

Abstracts of papers cited:

Biochem Pharmacol. 2010 Oct 15;80(8):1201-9. Epub 2010 Jul 6.
Glial cell line-derived neurotrophic factor induces cell migration and matrix metalloproteinase-13 expression in glioma cells.
Lu DY, Leung YM, Cheung CW, Chen YR, Wong KL.
Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, Taiwan.
Abstract
Malignant gliomas are the most common primary brain tumors in adults and the second most common tumor in children. Gliomas are associated high morbidity and mortality because these tumors are highly invasive into surrounding brain tissue, making complete surgical resection impossible. Glial cell line-derived neurotrophic factor (GDNF) has been identified as a potent neurotrophic factor in a variety of neuronal cell populations. However, the molecular mechanisms and pathologic roles underlying GDNF-induced glioma migration remain unclear. In this study, we found that application of recombinant human GDNF enhances the migration of U87 and U251 cells but not C6 cells. In addition, we found that the expression of matrix metalloproteinase-13 (MMP-13) mRNA, protein and secretion increase in response to GDNF stimulation. The GDNF-induced increase in cell migration was antagonized by MMP-13 neutralizing antibody or silencing MMP-13. We then examined the involvement of mitogen-activated protein kinases (MAPKs) in glioma cell migration induced by GDNF. GDNF-induced MMP-13 expression and glioma migration were attenuated by MEK/extracellular signal-regulating kinase (ERK) and c-Jun N-terminal protein kinase (JNK) inhibitors, as well as ERK and JNK dominant-negative mutants. Treatment with GDNF-induced MEK/ERK and JNK/c-Jun activation and increased AP-1 DNA binding activity in a time-dependent manner. Treatment with AP-1 inhibitors (tanshinone IIA and curcumin) also reduced GDNF-induced glioma cell migration. In migration-prone sublines, cells with greater migration ability had higher GDNF expression. These results indicate that GDNF enhances migration of glioma cells through the increase of MMP-13 production and is mainly regulated by the MEK/ERK and JNK, c-Jun and AP-1 pathways.

Neurosci Res. 2006 Sep;56(1):29-38. Epub 2006 Jun 30.
Glial cell-derived neurotrophic factor (GDNF) promotes low-grade Hs683 glioma cell migration through JNK, ERK-1/2 and p38 MAPK signaling pathways.
Song H, Moon A.
College of Pharmacy, Duksung Women's University, 419 Ssangmun-Dong, Dobong-Gu, Seoul, Republic of Korea.
Abstract
Invasion of tumor cells is the primary cause of therapeutic failure in the treatment of malignant gliomas. In an attempt to investigate the properties of the malignant progression of glioma cells, we examined the correlation between cell migration and glial cell-derived neurotrophic factor (GDNF) secretion of two glioma cell lines which differ in their invasive phenotypes. Here, we show that the high-grade C6 cells are more migrative and secrete more GDNF than the low-grade Hs683 cells. GDNF signaling is more highly activated in C6 cells than in Hs683 cells. Treatment of the Hs683 cells with GDNF significantly increased migration comparable to the C6 cells, revealing the autocrine and/or paracrine effect of GDNF on promotion of the glioma cell migration. We then examined the involvement of mitogen-activated protein kinases (MAPKs) including c-Jun N-terminal protein kinase (JNK), extracellular signal-regulated kinases (ERKs) and p38 MAPK in Hs683 cell migration induced by GDNF. A prominent activation of JNK, ERKs and p38 MAPK was observed in the GDNF-treated cells. Functional studies showed that the activation of these MAPKs was critical for Hs683 cell migration induced by GDNF. Our findings revealing molecular mechanisms for the promoting effect of GDNF on glioma cell migration may provide an insight into a better understanding to the malignant progression of human gliomas.

Neurosci Res. 2006 Sep;56(1):29-38. Epub 2006 Jun 30.
Glial cell-derived neurotrophic factor (GDNF) promotes low-grade Hs683 glioma cell migration through JNK, ERK-1/2 and p38 MAPK signaling pathways.
Song H, Moon A.
College of Pharmacy, Duksung Women's University, 419 Ssangmun-Dong, Dobong-Gu, Seoul, Republic of Korea.
Abstract
Invasion of tumor cells is the primary cause of therapeutic failure in the treatment of malignant gliomas. In an attempt to investigate the properties of the malignant progression of glioma cells, we examined the correlation between cell migration and glial cell-derived neurotrophic factor (GDNF) secretion of two glioma cell lines which differ in their invasive phenotypes. Here, we show that the high-grade C6 cells are more migrative and secrete more GDNF than the low-grade Hs683 cells. GDNF signaling is more highly activated in C6 cells than in Hs683 cells. Treatment of the Hs683 cells with GDNF significantly increased migration comparable to the C6 cells, revealing the autocrine and/or paracrine effect of GDNF on promotion of the glioma cell migration. We then examined the involvement of mitogen-activated protein kinases (MAPKs) including c-Jun N-terminal protein kinase (JNK), extracellular signal-regulated kinases (ERKs) and p38 MAPK in Hs683 cell migration induced by GDNF. A prominent activation of JNK, ERKs and p38 MAPK was observed in the GDNF-treated cells. Functional studies showed that the activation of these MAPKs was critical for Hs683 cell migration induced by GDNF. Our findings revealing molecular mechanisms for the promoting effect of GDNF on glioma cell migration may provide an insight into a better understanding to the malignant progression of human gliomas.

J Neurochem. 2010 Aug 27. [Epub ahead of print]
A specific isoform of GDNF family receptor alpha 1 regulates RhoA expression and glioma cell migration.
Wan G, Too HP.
Department of Biochemistry, National University of Singapore, Singapore 119260.
Abstract
Abstract Malignant gliomas are highly invasive neuroepithelial tumors where the tendency to invade and migrate away from the primary tumor mass is thought to be a leading cause of tumor recurrence and treatment failures. Autocrine signals produced by secreted factors that signal through receptors on the tumor are known to contribute to the invasiveness. Glial cell line-derived neurotrophic factor (GDNF) and its receptor GFRalpha1 are overexpressed in human gliomas. We have previously reported that human gliomas express high levels of GFRalpha1b, an alternatively spliced isoform of GFRalpha1. However, the functional significance of GFRalpha1b in glioma behaviors is currently unknown. In this study, we have designed isoform-specific siRNA to knockdown the highly homologous GFRalpha1a or GFRalpha1b isoform efficiently in malignant C6 glioma cells. Unexpectedly, the knockdown of GFRalpha1b but not GFRalpha1a induced cell elongation and inhibited C6 cell migration and invasion in vitro.
In addition, GFRalpha1b was found to regulate the expression of RhoA small GTPase, which was required for migration of C6 cells. The decreases in RhoA expression and cell migration after GFRalpha1b knockdown were attenuated by siRNA-resistant GFRalpha1b but not GFRalpha1a, further demonstrating the specific role of GFRalpha1b in glioma migration. Interestingly, the knockdown of NCAM but not receptor tyrosine kinase Ret resulted in the reduction of RhoA expression and C6 cell migration. Taken together, these unanticipated results indicate that GFRalpha1b is involved in glioma migration through GDNF-GFRalpha1b-NCAM signaling complex and modulation of RhoA expression.

J Pharmacol Exp Ther. 2007 Apr;321(1):148-57. Epub 2007 Jan 8.
Antidepressants increase glial cell line-derived neurotrophic factor production through monoamine-independent activation of protein tyrosine kinase and extracellular signal-regulated kinase in glial cells.
Hisaoka K, Takebayashi M, Tsuchioka M, Maeda N, Nakata Y, Yamawaki S.
Institute of Clinical Research, Kure Medical Center, 3-1 Aoyama, Kure 737-0023, Japan.
Abstract
Recent studies show that neuronal and glial plasticity are important for therapeutic action of antidepressants. We previously reported that antidepressants increase glial cell line-derived neurotrophic factor (GDNF) production in rat C6 glioma cells (C6 cells). Here, we found that amitriptyline, a tricyclic antidepressant, increased both GDNF mRNA expression and release, which were selectively and completely inhibited by mitogen-activated protein kinase kinase inhibitors. Indeed, treatment of amitriptyline rapidly increased extracellular signal-regulated kinase (ERK) activity, as well as p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase activities. Furthermore, different classes of antidepressants also rapidly increased ERK activity. The extent of acute ERK activation and GDNF release were significantly correlated to each other in individual antidepressants, suggesting an important role of acute ERK activation in GDNF production. Furthermore, antidepressants increased the acute ERK activation and GDNF mRNA expression in normal human astrocytes as well as C6 cells. Although 5-hydroxytryptamine (serotonin) (5-HT), but not noradrenaline or dopamine, increased ERK activation and GDNF release via 5-HT2A receptors, ketanserin, a 5-HT2A receptor antagonist, did not have any effect on the amitriptyline-induced ERK activation. Thus, GDNF production by amitriptyline was independent of monoamine. Both of the amitriptyline-induced ERK activation and GDNF mRNA expression were blocked by genistein, a general protein tyrosine kinase (PTK) inhibitor. Actually, we found that amitriptyline acutely increased phosphorylation levels of several phosphotyrosine-containing proteins. Taken together, these findings indicate that ERK activation through PTK regulates antidepressant-induced GDNF production and that the GDNF production in glial cells may be a novel action of the antidepressant, which is independent of monoamine.
PMID: 17210798


J Neurochem. 2008 Jul;106(1):244-57. Epub 2008 Jul 1.
Serotonin (5-HT) induces glial cell line-derived neurotrophic factor (GDNF) mRNA expression via the transactivation of fibroblast growth factor receptor 2 (FGFR2) in rat C6 glioma cells.
Tsuchioka M, Takebayashi M, Hisaoka K, Maeda N, Nakata Y.
Division of Psychiatry and Neuroscience, Institute of Clinical Research, National Hospital Organization (NHO), Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
Abstract
We previously reported that serotonin (5-HT) increased glial cell line-derived neurotrophic factor (GDNF) release in a 5-HT(2) receptor (5-HT(2)R) and mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK)-dependent manner in rat C6 glioma cells (C6 cells), a model of astrocytes. We herein found that 5-HT-induced rapid ERK phosphorylation was blocked by 5-HT(2)R antagonists in C6 cells. We therefore examined 5-HT-induced ERK phosphorylation to reveal the mechanism of 5-HT-induced GDNF mRNA expression. As 5-HT-induced ERK phosphorylation was blocked by inhibitors for Galpha(q/11) and fibroblast growth factor receptor (FGFR), but not for second messengers downstream of Galpha(q/11), 5-HT(2)R-mediated FGFR transactivation was suggested to be involved in the ERK phosphorylation. Although FGFR1 and 2 were functionally expressed in C6 cells, 5-HT selectively phosphorylated FGFR2. Indeed, small interfering RNA for FGFR2, but not for FGFR1, blocked 5-HT-induced ERK phosphorylation. As Src family tyrosine kinase inhibitors and microtubule depolymerizing agents blocked 5-HT-induced FGFR2 phosphorylation, Src family tyrosine kinase and stabilized microtubules were suggested to act upstream of FGFR2. Finally, 5-HT-induced GDNF mRNA expression was also inhibited by the blockade of 5-HT(2)R, FGFR, and Src family tyrosine kinase. In conclusion, our findings suggest that 5-HT induces GDNF mRNA expression via 5-HT(2)R-mediated FGFR2 transactivation in C6 cells.
PMID: 18363829 [

Anticancer Res. 2010 Feb;30(2):391-7.
The in vitro effects of tricyclic drugs and dexamethasone on cellular respiration of malignant glioma.
Higgins SC, Pilkington GJ.
Cellular and Molecular Neuro-oncology Group, Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, White Swan Road, University of Portsmouth, Portsmouth, Hampshire PO1 2DT, UK.
Abstract
BACKGROUND: In this investigation the effects of tricyclic drugs on cellular respiration were studied using the anaplastic astrocytoma cell line IPSB-18 by use of a Clark-type oxygen electrode which measured changes in cellular respiration rate (oxygen consumption), in a dose-response assay.
MATERIALS AND METHODS: The drugs investigated were clomipramine, norclomipramine, amitriptyline and doxepin. In addition, the combined effects of dexamethasone and clomipramine on cellular respiration were investigated.
RESULTS: It was established that at lower concentrations (0.14 mM-0.5 mM) amitriptyline was the most potent inhibitor of cellular respiration. Previous studies have indicated that inhibition of cellular respiration is considered an indicator of apoptosis. Overall, it appeared that clomipramine and its metabolite norclomipramine were the most potent inhibitors of cellular respiration in glioma cells over the concentration range 0.5-0.9 mM. Dexamethasone was able to induce inhibition of cellular respiration both alone in glioma cells, and in combination with clomipramine, where it had an additive or synergistic effect, thereby increasing cell death.
CONCLUSION: The extensive research currently ongoing and previously reported regarding the use of clomipramine as a potential antineoplastic agent aimed at targeting the mitochondria of gliomas is promising.

Neuroscience. 2000;96(2):417-25.
Dexamethasone pre-treatment interferes with apoptotic death in glioma cells.
Gorman AM, Hirt UA, Orrenius S, Ceccatelli S.
Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institute, Box 210, S-171 77, Stockholm, Sweden.
Abstract
Glucocorticoids are known to influence the ability of cells to undergo apoptosis, directly inducing apoptosis in thymocytes while inhibiting it in hepatoma and carcinoma cells. Dexamethasone, a synthetic glucocorticoid, is reported to induce partial resistance to certain anticancer drugs in glioma cell lines. In the present study, the effect of dexamethasone on apoptosis of glioma and astrocytoma cell lines was investigated. Exposure of D384 human astrocytoma and C6 rat glioma cells to staurosporine induced apoptosis as judged by the formation of condensed nuclei and caspase activation. Pre-treatment of cells with dexamethasone caused a reduction in staurosporine-induced apoptosis. In addition, dexamethasone also conferred protection against the induction of apoptosis by anticancer agents including camptothecin and etoposide. The protective effect of dexamethasone was dose and time dependent, with maximal protection obtained with concentrations equal to or greater than 100 nM and a pre-incubation period of at least 24h. The earliest significant inhibition was seen with a pre-incubation period of 8h. Co-treatment with the glucocorticoid receptor antagonist RU38486 abolished the effect of dexamethasone, indicating that the protection due to dexamethasone is mediated via this receptor. Dexamethasone was found to induce a time-dependent up-regulation of Bcl-x(L) protein expression. However, the ability of cytochrome c/dATP to activate the caspase cascade in cytosolic extracts of D384 cells was unaffected by prior exposure of the cells to dexamethasone (1 microM) for 48 h. In conclusion, dexamethasone inhibits the induction of apoptosis in astrocytoma cells, probably via an up-regulation of Bcl-x(L), which could prevent cytochrome c release from mitochondria and subsequent caspase activation. Since glucocorticoids are often used in the treatment of gliomas to relieve cerebral oedema, the inhibition of apoptosis by these compounds could potentially interfere with the efficacy of chemotherapeutic drugs.

Apoptosis. 2006 Jul;11(7):1247-55.
Dexamethasone inhibits apoptosis in C6 glioma cells through increased expression of Bcl-XL.
Ní Chonghaile T, Concannon CG, Szegezdi E, Gorman AM, Samali A.
Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland.
Abstract
The glucocorticoid dexamethasone (Dex) has been reported to modulate a number of signaling pathways and physiological processes, including apoptosis. This study was carried out to investigate the cytoprotective mechanism of Dex in C6 glioma cells. Pre-treatment of cells with Dex inhibited apoptosis induced by staurosporine, etoposide and thapsigargin. Apoptosis inhibition correlated with blockade of mitochondrial cytochrome c release, abolition of caspase-3 activity along with inhibition of caspase-9 and PARP cleavage. Dex-mediated cytoprotection coincided with the induction of the anti-apoptotic protein, Bcl-X(L). The specific glucocorticoid receptor antagonist, RU486, reversed the anti-apoptotic effect of Dex and prevented Bcl-X(L) induction. Here, we show for the first time that knockdown of Bcl-X(L) expression with siRNA reversed the protective effects of the glucocorticoid in glioma cells. We conclude that Dex-mediated inhibition of apoptosis in C6 glioma cells is through
induction of Bcl-X(L).
PMID: 16699951

Biochim Biophys Acta. 2009 May;1793(5):764-71. Epub 2009 Feb 7.
Dexamethasone inhibits camptothecin-induced apoptosis in C6-glioma via activation of Stat5/Bcl-xL pathway.
Qian YH, Xiao Q, Chen H, Xu J.
Department of Human Anatomy and Histology-Embryology, School of Medicine, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Abstract
Dexamethasone (DX) induces apoptosis resistance in most solid malignant tumors during co-treatment with chemotherapy agents, such as camptothecin (CAM). In this study, we investigated the mechanism by which DX reduces chemotherapy efficiency in C6-glioma. DX reduced CAM-increased DNA fragmentation and caspase-3 activation. The DX's protection was negated by RU486, an antagonist of glucocorticoid receptor (GR). DX itself increased anti-apoptotic gene, Bcl-xL expression, and its transcription factor, signaling transducer and activator of transcription 5 (Stat5), DNA binding activity and phospho-Stat5 expression. DX blocked the CAM-decreased Bcl-xL and phospho-Stat5 expression, and Stat5 binding activity. RU486 negated DX's actions. To determine whether Stat5 regulates Bcl-xL expression in CAM-induced cell death, C6-glioma was infected with an adenovirus containing a constitutively activated Stat5-GFP (Ad-Stat5ca). Overexpression of Stat5ca increased Bcl-xL and decreased CAM-induced cell death compared to control adenovirus infected cells; whereas Stat5 siRNA decreased DX-induced Bcl-xL and increased cell death. Phospho-Stat5 expression was observed in the nuclear extract by co-immunoprecipitation with an anti-GR antibody, indicating that Stat5 and GR were interactive and formed a complex in the nuclei. These results suggest that DX's prevention from CAM-induced apoptosis and RU486's antagonism of DX's protection may be through Stat5/Bcl-xL signal pathway regulated by a GR.

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