olanzapine and Glioma

Radiotherapy is used as one of the most effective regimens for cancer treatment, while radioresistance is a major drawback in cancer treatment.. This study aimed to evaluate the sensitizing effect of olanzapine (OLA) with X-ray on glioblastoma (U-87 MG) cells death.. The synergistic killing effect of OLA with ionizing radiation (IR) on glioma was evaluated by colony formation assay. The generations of reactive oxygen species (ROS) and protein carbonyl (PC) as oxidized proteins were determined in OLA-treated and irradiated cells.. Results of this study showed that OLA reduced the number of colonies in irradiated glioma cells.OLA elevated ROS and PC levels in irradiated cells. The synergistic killing effect of OLA with IR in U-87 MG cells was observed at concentrations of 1 μM and 20 μM of OLA. The maximum radiosensitizing effect of OLA was observed at a concentration of 20 μM.. The present study demonstrates that OLA has a radiosensitizing effect on cell death induced by IR in glioma cells.

Topics: Antipsychotic Agents; Cell Line, Tumor; Glioblastoma; Glioma; Humans; Olanzapine; Radiation-Sensitizing Agents; Radiopharmaceuticals; Reactive Oxygen Species

Our laboratory previously reported that olanzapine treatment inhibited growth of glioma cell lines and hypothesized that autophagy may be involved in the proliferation inhibitory effects of olanzapine. However, the mechanisms of olanzapine-contributed autophagy activation are unclear.. The inhibitory effects of olanzapine on glioma cells were evaluated by CCK8 assay, Hoechst 33258 staining and annexin V-FITC/PI staining. Western blotting, nuclear separation techniques, and immunofluorescence assays were used to investigate the relationship between the inhibition of NF-κB and autophagy activation by olanzapine.. In this work, we verified that olanzapine increased autophagic flux and autophagic vesicles. In addition, we confirmed that autophagy was related to NF-κB inhibition in cancer progression, especially with the nuclear translocation of p65. Furthermore, we demonstrated that autophagy induced by olanzapine could be impaired with TNFα cotreatment. We also found that olanzapine had an inhibitory effect on T98 cells with positive MGMT protein expression, which may involve the inhibition of MGMT through effects on NF-κB.. Our findings identify a pathway by which olanzapine induces autophagy by depressing NF-κB in a glioma cell line, providing evidence which supports the use of olanzapine as a potential anticancer drug.

Topics: Antineoplastic Agents; Autophagy; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Glioma; Humans; NF-kappa B; Olanzapine; Selective Serotonin Reuptake Inhibitors

Olanzapine, a D2/5-HT2 antagonist, is often used as an atypical antipsychotic drug in clinical. Previous research has found its new pharmacological influence on enhancing the differentiation of neural stem cells (NSCs) to oligodendrocyte-like cells (ODLCs). Glioblastomas are associated with poor prognoses owing to the glioma stem-like cells (GSLCs), which have a great many of similarities with adult NSCs. Hence, in this article, we aim to study the effects and associated mechanisms of olanzapine on GSLCs derived from human U87MG glioblastoma cell lines.. The methyl thiazolyl tetrazolium (MTT) colorimetric assay was conducted to investigate the effects of olanzapine on cell viability of GSLCs. Flow cytometric analysis was applied to study the cell cycle dynamics of GSLCs and Cell Counting Kit-8 (CCK-8) was used to further investigate the proliferation of GSLCs after treated with olanzapine or dimethyl sulfoxide (DMSO) for 48 h. Cell differentiation assay was carried out to study the differentiation of GSLCs and then Image-Pro Plus image analysis was used to measure the protrusion length of the differentiated cells. Furthermore, the confocal [Ca2+]c measurement was conducted to observe the influence of olanzapine on the opening function of Ca2+ channel. After the application of olanzapine for 48 h, RT-PCR was conducted to measure mRNA levels of calcium-sensing receptor (CaSR) and stromal interaction molecule 1 (STIM1), and Western blotting analysis was carried out to examine the expression of myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), CaSR protein, STIM1 protein and β-catenin protein.. Our results demonstrated that olanzapine inhibited the proliferation of GSLCs by arresting cell cycle in G0/G1 phase and facilitated the differentiation of such cells to ODLCs. After treated with olanzapine for 48 h, cells were very sensitive to 100 mM K+ stimulation, with increased spontaneous calcium wave. We also found olanzapine increased the protein expression of MBP and GFAP. In addition, the mRNA transcription and protein expression of CaSR and STIM1 were enhanced after treated with olanzapine for 48h, while the protein expression of β-catenin was suppressed.. Our results suggest that olanzapine modulates the Wnt signaling pathway through activating the Ca2+ pathway and restraining the β-catenin pathway, leading to the differentiation of GSLCs to ODLCs. It provides exciting prospects that olanzapine might be a new novel chemotherapeutic modality targeting GSLCs for the treatment of glioblastomas.

Topics: Benzodiazepines; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Glioma; Humans; Neoplastic Stem Cells; Olanzapine; Selective Serotonin Reuptake Inhibitors; Wnt Signaling Pathway

The aim of this study was to investigate the effects of olanzapine on growth inhibition as well as autophagy in glioma cells in vitro and in vivo. The proliferation of both LN229 and T98 glioma cells, measured by MTT assay, was suppressed in a concentration-dependent and time-dependent manner. Moreover, apoptosis of both cells was significantly increased with the treatment of olanzapine as evidenced by increased Bcl-2 expression, Hoechst 33258 staining and annexinV-FITC/PI staining. Olanzapine treatment also enhanced activation of autophagy with increased expression of LC3-II, expression of protein p62, a substrate of autophagy, being decreased. The growth inhibition by olanzapine in both glioma cell lines could be blocked by co-treatment with 3-MA, an autophagy inhibitor. Furthermore, olanzapine effectively blocked the growth of subcutaneous xenografts of LN229 glioma cells in vivo. The increased level of protein LC3-II and decreased level of p62 followed by a decreased level of Bcl-2, suggesting that autophagy may contribute to apoptosis. In addition, reduced proliferation of glioma cells was shown by a decrease of Ki-67 staining and increased caspase-3 staining indicative of apoptosis in mouse xenografts. These results indicated that olanzapine inhibited the growth of glioma cells accompanied by induction of autophagy and apoptosis both in vitro and in vivo. Olanzapine-induced autophagy plays a tumor-suppressing role in glioma cells.

Topics: Animals; Apoptosis; Autophagy; Benzodiazepines; Biomarkers, Tumor; Blotting, Western; Brain Neoplasms; Cell Proliferation; Flow Cytometry; Glioma; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Olanzapine; Selective Serotonin Reuptake Inhibitors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays