quetiapine-fumarate and Glioma

As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs. Our data demonstrated that (i) QUE monotherapy can effectively suppress GSCs-initiated tumor growth; (ii) QUE has synergistic effects with temozolomide (TMZ) on glioma suppression, and importantly, QUE can effectively suppress TMZ-resistant (or -escaped) tumors generated from GSCs; (iii) mechanistically, the anti-glioma effect of QUE was due to its actions of promoting the differentiation of GSCs into oligodendrocyte (OL)-like cells and its inhibitory effect on the Wnt/β-catenin signaling pathway. Together, our findings suggest an effective approach for anti-gliomagenic treatment via targeting OL-oriented differentiation of GSCs. This also opens a door for repurposing QUE, an FDA approved drug, for the treatment of malignant glioma.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Differentiation; Cell Line, Tumor; Dacarbazine; Drug Repositioning; Drug Synergism; Glioma; Humans; Mice, Inbred C57BL; Mice, Nude; Neoplasms, Experimental; Neoplastic Stem Cells; Oligodendroglia; Quetiapine Fumarate; Temozolomide; Tumor Burden

Quetiapine is an atypical antipsychotic which has been suggested to possess also antidepressant efficacy in the treatment of bipolar and unipolar depression. Recently, a link between the activation of the ERK/MAPK signalling pathway and the release of GDNF has been proposed as a specific feature of antidepressants. To obtain a first insight into the putative molecular mechanism of action of quetiapine, we examined its impact and that of its major metabolite norquetiapine on the activation of the ERK/MAPK signalling pathway in C6 glioma cells. Additionally, we investigated the induction of GDNF release as a possible physiological consequence of this activation. We found that norquetiapine, similarly to the antidepressant reboxetine, activated both ERK1 and ERK2 (pERK) with consequent enhanced release of GDNF; this release was dependent on pERK, as demonstrated by its reversibility after pre-treatment with a pharmacological pERK inhibitor. In contrast, quetiapine induced activation of ERK2 only. It also caused release of GDNF, but this release was independent of ERK activation. To test whether the simultaneous activation of ERK1 with ERK2 was critical for the observed pERK-dependent GDNF release, we specifically inactivated ERK1 mRNA via RNA interference. Our data show that indeed ERK1 plays an essential role, as GDNF release was hampered after Erk1 downregulation comparably to a pharmacological pERK inhibitor. Thus, activation of only ERK2 appears not to be sufficient for promoting GDNF release. Our results reveal the release of GDNF as a consequence of ERK/MAPK signalling activation by norquetiapine, which may contribute to the putative antidepressant properties of quetiapine. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Topics: Animals; Antidepressive Agents; Cell Line, Tumor; Dibenzothiazepines; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic; Glial Cell Line-Derived Neurotrophic Factor; Glioma; Lactate Dehydrogenases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Propylamines; Pyridines; Quetiapine Fumarate; Rats; RNA, Messenger; RNA, Small Interfering; Transfection

Atypical antipsychotic drugs have been shown to protect PC12 cells from cell death induced by a variety of stimuli in culture. Recently, it has been postulated that trophic factors, such as brain-derived neurotrophic factor (BDNF), play a role in preventing cell death. It has been shown that antipsychotic drugs attenuate the decrease in rat hippocampal BDNF that results from immobilization-induced stress. We aimed to determine whether the neuroprotective effects of antipsychotic drugs could be mediated through glial cell line-derived neurotrophic factor (GDNF).. We investigated the effects of the atypical antipsychotic drugs quetiapine and clozapine and the typical antipsychotic haloperidol on the secretion of GDNF from rat C6 glioma cells.. All 3 drugs increased the amount of GDNF secreted from C6 glioma cells into the medium after 48-hour culture. The intracellular content of GDNF was not altered by treatment with any of the antipsychotic drugs. None of the antipsychotic drugs decreased cell number.. This study suggests that stimulation of GDNF release from glial cells by antipsychotic drugs might underlie some of their neuroprotective properties in situ.

Topics: Animals; Antipsychotic Agents; Cell Line, Tumor; Clozapine; Dibenzothiazepines; Enzyme-Linked Immunosorbent Assay; Glial Cell Line-Derived Neurotrophic Factor; Glioma; Haloperidol; Hippocampus; Quetiapine Fumarate; Rats