olanzapine and Glioblastoma

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

The poor prognosis of patients with glioblastoma fuels the search for more effective therapeutic compounds. We previously hypothesised that the neuroleptic olanzapine may enhance antineoplastic effects of temozolomide the standard chemotherapeutic agent used in this disease. This study tested this hypothesis. The anti-proliferative effect of olanzapine was examined by MTT assays and cell count analysis. Soft-agar assays were performed to examine colony-forming ability. In addition, the inhibitory effect of olanzapine on the migratory capacity of U87MG and A172 cells was analyzed by Transwell(®) assays. Moreover, staining for annexin V/propidium iodide or carboxyfluorescein succinimidyl ester was performed prior to flow cytometric analysis in order to better understand the subjacent cellular mechanism. Our initial hypothesis that olanzapine may enhance temozolomide's anti-tumor activity could be confirmed in U87MG and A172 glioblastoma cell lines. Moreover, treatment with olanzapine alone resulted in a marked anti-proliferative effect on U87MG, A172 and two glioma stem-like cells with IC50 values ranging from 25 to 79.9 µM. In U87MG cells, anchorage-independent growth was dose-dependently inhibited. In A172 cells, migration was also shown to be inhibited in a dose-dependent manner. In addition, olanzapine was shown to exert a cell line-dependent pleomorphism with respect to the induction of apoptosis, necrosis and/or cytostasis. Our data show that the neuroleptic olanzapine enhances the anti-tumor activity of temozolomide against glioblastoma cell lines. Moreover, this is the first study to show that olanzapine provides on its own anti-cancer activity in glioblastoma and thus may have potential for repurposing.

Topics: Antineoplastic Agents, Alkylating; Antipsychotic Agents; Apoptosis; Benzodiazepines; Blotting, Western; Brain Neoplasms; Cell Adhesion; Cell Movement; Cell Proliferation; Dacarbazine; Drug Synergism; Glioblastoma; Humans; Olanzapine; Phosphoproteins; Protein Array Analysis; Temozolomide; Tumor Cells, Cultured

As current treatments for glioblastoma commonly fail to cure, the need for more effective therapeutic options is overwhelming. Here, we summarize experimental evidence in support of the suggestion that metformin and olanzepine have potential to enhance the cytotoxic effects of temozolomide, an alkylating chemotherapeutic agent commonly used to treat glioblastoma. Although the primary path leading to temozolomide-induced cell death is formation of O-6-methylguanine and apoptotic signalling triggered by O-6-methyl G:T mispairs, that apoptotic signalling goes through a step mediated by AMP-activated protein kinase (AMPK). Metformin or olanzapine have been shown independently to enhance AMPK activation. Metformin to treat diabetes and olanzapine to treat psychiatric disorders are well tolerated and have been used clinically for many years. Thus it should be feasible to increase AMPK activation and add to the pro-apoptotic effects of temozolomide, by adding metformin and olanzapine to the therapeutic regimen. Clinical assessment of the potential benefit of such combined therapy against glioblastoma is warranted.

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents, Alkylating; Apoptosis; Benzodiazepines; Brain Neoplasms; Cell Line, Tumor; Dacarbazine; Energy Metabolism; Enzyme Activation; Glioblastoma; Humans; Metformin; Olanzapine; Temozolomide