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Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination

三氟拉嗪 自噬 癌症研究 辐射敏感性 体内 克隆形成试验 替莫唑胺 组织蛋白酶D 化学 生物 药理学 细胞凋亡 放射治疗 医学 胶质瘤 内科学 生物化学 生物技术 钙调蛋白
作者
Xin Zhang,Ran Xu,Chao Zhang,Yangyang Xu,Mingzhi Han,Bin Huang,Anjing Chen,Chen Qiu,Frits Thorsen,Lars Prestegarden,Rolf Bjerkvig,Jian Wang,Xingang Li
出处
期刊:Journal of Experimental & Clinical Cancer Research [Springer Nature]
卷期号:36 (1) 被引量:47
标识
DOI:10.1186/s13046-017-0588-z
摘要

Resistance to adjuvant radiotherapy is a major cause of treatment failure in patients with glioblastoma (GBM). Autophagy inhibitors have been shown to enhance the efficacy of radiotherapy for certain solid tumors. However, current inhibitors do not penetrate the blood-brain-barrier (BBB). Here, we assessed the radiosensitivity effects of the antipsychotic drug trifluoperazine (TFP) on GBM in vitro and in vivo.U251 and U87 GBM cell lines as well as GBM cells from a primary human biopsy (P3), were used in vitro and in vivo to evaluate the efficacy of TFP treatment. Viability and cytotoxicity was evaluated by CCK-8 and clonogenic formation assays. Molecular studies using immunohistochemistry, western blots, immunofluorescence and qPCR were used to gain mechanistic insight into the biological activity of TFP. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models.IC50 values of U251, U87 and P3 cells treated with TFP were 16, 15 and 15.5 μM, respectively. TFP increased the expression of LC3B-II and p62, indicating a potential disruption of autophagy flux. These results were further substantiated by a decreased Lysotracker Red uptake, indicating impaired acidification of the lysosomes. We show that TFP and radiation had an additive effect when combined. This effect was in part due to impaired TFP-induced homologous recombination. Mechanistically we show that down-regulation of cathepsin L might explain the radiosensitivity effect of TFP. Finally, combining TFP and radiation resulted in a significant antitumor effect in orthotopic GBM xenograft models.This study provides a strong rationale for further clinical studies exploring the combination therapy of TFP and radiation to treat GBM patients.
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