Abstract
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.
Highlights
Malignant glioma is one of the most common primary brain tumors in humans (Katsetos et al, 2007)
Olanzapine induced apoptosis in glioma cells Using western blot analysis, apoptosis was indicated by the decreased expression of Bcl-2 in glioma cells treated with olanzapine (Figure 2A and 2B)
Apoptotic cells with abnormal nuclear increased in LN229 and T98 cells treated with olanzapine (Figure 2C)
Summary
Malignant glioma is one of the most common primary brain tumors in humans (Katsetos et al, 2007). Multi-modality treatments, including surgery, radiation and chemotherapy, exist for this aggressive tumor, the prognosis of patients remains unfavorable (Stupp et al, 2009). Most patients die within 2 years even under the standard combined therapy of radiotherapy and the alkylating agent temozolomide (TMZ), which is a standard chemotherapeutic drug for the firstline treatment of glioblastoma (Stupp et al, 2009). The resistance to TMZ becomes an obstacle for the success of glioblastoma therapy such as IDH1 overexpression occurred in glioma parents displayed chemotherapy resistance characteristic in TMZ induced invasion and apoptosis inhibition (Wang et al, 2014). An effective anti-glioblastoma drug is urgently needed in order to create life-changing therapeutics for brain cancer patients, especially for those resistant to TMZ
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