Inhibition of Elongation Factor-2 Kinase Augments the Antitumor Activity of Temozolomide against Glioma |
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| Authors: | Xiao-yuan Liu Li Zhang JianPing Wu Lei Zhou Yi-Jie Ren Wei-Qiong Yang Zi-Jun Ming Bo Chen Jianrong Wang Yi Zhang Jin-Ming Yang |
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| Affiliation: | 1. Department of Pharmacology, College of Pharmaceutical Sciences, Cyrus Tang Hematology Center, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu, China.; 2. Department of Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.; University of Chicago, United States of America, |
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| Abstract: | BackgroundGlioblastoma multiforme (GBM), the most common form of brain cancer with an average survival of less than 12 months, is a highly aggressive and fatal disease characterized by survival of glioma cells following initial treatment, invasion through the brain parenchyma and destruction of normal brain tissues, and ultimately resistance to current treatments. Temozolomide (TMZ) is commonly used chemotherapy for treatment of primary and recurrent high-grade gliomas. Nevertheless, the therapeutic outcome of TMZ is often unsatisfactory. In this study, we sought to determine whether eEF-2 kinase affected the sensitivity of glioma cells to treatment with TMZ. Methodology/Principal FindingsUsing RNA interference approach, a small molecule inhibitor of eEF-2 kinase, and invitro and invivo glioma models, we observed that inhibition of eEF-2 kinase could enhance sensitivity of glioma cells to TMZ, and that this sensitizing effect was associated with blockade of autophagy and augmentation of apoptosis caused by TMZ.Conclusions/SignificanceThese findings demonstrated that targeting eEF-2 kinase can enhance the anti-glioma activity of TMZ, and inhibitors of this kinase may be exploited as chemo-sensitizers for TMZ in treatment of malignant glioma. |
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