Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule (Retracted article. See vol. 170, pg. 407, 2017)
Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule (Retracted article. See vol. 170, pg. 407, 2017)
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DOI：
10.1016/j.cell.2014.02.021
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发表时间：
2014-04-10
期刊：
影响因子：
64.5
通讯作者：
Ernfors, Patrik
中科院分区：
文献类型：
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作者：
Kitambi, Satish Srinivas;Toledo, Enrique M.;Ernfors, Patrik
多形性胶质母细胞瘤(GBM)是最具侵袭性的脑癌，平均寿命较低。基于GBM细胞获得的功能不一定参与癌症过程的假设，对患者来源的胶质母细胞瘤细胞(GC)进行筛选，以确定适合于开发靶向治疗的细胞过程。奎宁衍生物NSC13316可靠和选择性地损害了生存能力。合成的化学膨胀显示了微妙的结构-活性关系和效力增加的类似物，称为Vacquinol。Vacquinol通过膜皱折、细胞变圆、大量巨噬细胞空泡堆积、ATP耗竭和细胞质膜破裂等方式刺激细胞死亡。经shRNA筛选鉴定的MAP激酶MKK4代表一个关键的信号转导节点。在GBM动物模型中，Vacquol-1表现出良好的体内药代动力学和脑暴露，延缓疾病进展，延长存活时间。这些结果确定了一个可被小分子靶向的大规模空泡化的脆弱性，并指出了在抗癌治疗设计中可能利用这一过程。
Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with marginal life expectancy. Based on the assumption that GBM cells gain functions not necessarily involved in the cancerous process, patient-derived glioblastoma cells (GCs) were screened to identify cellular processes amenable for development of targeted treatments. The quinine-derivative NSC13316 reliably and selectively compromised viability. Synthetic chemical expansion reveals delicate structure-activity relationship and analogs with increased potency, termed Vacquinols. Vacquinols stimulate death by membrane ruffling, cell rounding, massive macropinocytic vacuole accumulation, ATP depletion, and cytoplasmic membrane rupture of GCs. The MAP kinase MKK4, identified by a shRNA screen, represents a critical signaling node. Vacquinol-1 displays excellent in vivo pharmacokinetics and brain exposure, attenuates disease progression, and prolongs survival in a GBM animal model. These results identify a vulnerability to massive vacuolization that can be targeted by small molecules and point to the possible exploitation of this process in the design of anticancer therapies.