Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada.
Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada
Anticancer Res. 2014 Sep;34(9):4915-27.
BACKGROUND/AIM: The heat-shock proteins HSP27 and HSP90 perpetuate the malignant nature of glioblastoma multiforme (GBM) and offer promise as targets for novel cancer therapeutics. The present study sought to define synergistic antitumor benefits of concurrent HSP27-knockdown and the HSP90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) or, comparatively, the non-selective kinase inhibitor, staurosporine, in GBM cells.
Dose-response relations were determined for 17-AAG and staurosporine in three GBM cell lines. HSP27-targeted siRNA was administered alone or in combination with subtherapeutic concentrations of each drug and cells were evaluated for viability, proliferation and apoptosis.
Adjuvant HSP27 knockdown with 17-AAG or staurosporine produced marked and synergistic decrease in GBM cell viability and proliferation, with robust elevation of apoptotic fractions and caspase-3 activation.
HSP27 knockdown confers potent chemosensitization of GBM cells. These novel data support the development of HSP-targeting strategies and, specifically, anti-HSP27 agents for the treatment of GBM.
背景/目的：热休克蛋白 HSP27 和 HSP90 使多形性胶质母细胞瘤（GBM）保持恶性特征，并为新型癌症治疗提供了有希望的靶点。本研究旨在确定 HSP27 敲低与 HSP90 抑制剂 17-N-烯丙基-17-去甲氧基格尔德霉素（17-AAG）或相对非选择性激酶抑制剂星形孢菌素在 GBM 细胞中协同抗肿瘤的益处。
在三种 GBM 细胞系中确定了 17-AAG 和星形孢菌素的剂量反应关系。单独或联合使用亚治疗浓度的每种药物给予 HSP27 靶向 siRNA，并评估细胞活力、增殖和凋亡。
用 17-AAG 或星形孢菌素辅助 HSP27 敲低可显著协同降低 GBM 细胞活力和增殖，凋亡分数显著升高，半胱天冬酶-3 激活。
HSP27 敲低可增强 GBM 细胞的化疗敏感性。这些新数据支持 HSP 靶向策略的发展，特别是用于治疗 GBM 的抗 HSP27 药物。
