Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
Neuro Oncol. 2010 May;12(5):473-81. doi: 10.1093/neuonc/nop048. Epub 2010 Jan 27.
Glioblastoma (GBM) is a high-grade central nervous system malignancy and despite aggressive treatment strategies, GBM patients have a median survival time of just 1 year. Chloroquine (CQ), an antimalarial lysosomotropic agent, has been identified as a potential adjuvant in the treatment regimen of GBMs. However, the mechanism of CQ-induced tumor cell death is poorly defined. We and others have shown that CQ-mediated cell death may be p53-dependent and at least in part due to the intrinsic apoptotic death pathway. Here, we investigated the effects of CQ on 5 established human GBM lines, differing in their p53 gene status. CQ was found to induce a concentration-dependent death in each of these cell lines. Although CQ treatment increased caspase-3-like enzymatic activity in all 5 cell lines, a broad-spectrum caspase inhibitor did not significantly attenuate death. Moreover, CQ caused an accumulation of autophagic vacuoles in all cell lines and was found to affect the levels and subcellular distribution of cathepsin D, suggesting that altered lysosomal function may also play a role in CQ-induced cell death. Thus, CQ can induce p53-independent death in gliomas that do not require caspase-mediated apoptosis. To potentially identify more potent chemotherapeutics, various CQ derivatives and lysosomotropic compounds were tested on the GBM cells. Quinacrine and mefloquine were found to be more potent than CQ in killing GBM cells in vitro and given their superior blood-brain barrier penetration compared with CQ may prove more efficacious as chemotherapeutic agents for GBM patients.
胶质母细胞瘤（GBM）是一种高级中枢神经系统恶性肿瘤，尽管采用了积极的治疗策略，但 GBM 患者的中位生存时间仅为 1 年。氯喹（CQ），一种抗疟溶酶体药物，已被确定为 GBM 治疗方案的潜在辅助药物。然而，CQ 诱导肿瘤细胞死亡的机制尚未明确。我们和其他人已经表明，CQ 介导的细胞死亡可能依赖于 p53，至少部分是由于内在的凋亡死亡途径。在这里，我们研究了 CQ 对 5 种已建立的人类 GBM 细胞系的影响，这些细胞系在其 p53 基因状态上有所不同。结果发现 CQ 以浓度依赖的方式诱导这些细胞系中的细胞死亡。尽管 CQ 处理增加了所有 5 种细胞系中的 caspase-3 样酶活性，但广谱半胱天冬酶抑制剂并不能显著减弱死亡。此外，CQ 在所有细胞系中引起自噬空泡的积累，并发现影响组织蛋白酶 D 的水平和亚细胞分布，这表明改变溶酶体功能也可能在 CQ 诱导的细胞死亡中发挥作用。因此，CQ 可以诱导不依赖于 caspase 的 p53 独立死亡，而不需要 caspase 介导的凋亡。为了潜在地鉴定更有效的化学治疗药物，对 GBM 细胞进行了各种 CQ 衍生物和溶酶体靶向化合物的测试。结果发现，喹啉和甲氟喹在体外杀伤 GBM 细胞的作用比 CQ 更强，并且由于它们与 CQ 相比具有更好的血脑屏障穿透性，因此可能作为 GBM 患者的化疗药物更有效。
