Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas.
Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas.
复制标题
新型化疗增敏剂 ERW1227B 会损害胶质母细胞瘤中的细胞运动并加速细胞死亡。
DOI：
10.1007/s11060-010-0379-2
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发表时间：
2011
影响因子：
3.9
通讯作者：
Rich,KeithM
中科院分区：
文献类型：
--
作者：
Yuan,Liya;Holmes,TracyC;Watts,REdward;Khosla,Chaitan;Broekelmann,TomJ;Mecham,Robert;Zheng,Hong;Izaguirre,EnriqueW;Rich,KeithM
胶质母细胞瘤表现出可变的表型，包括与增强的迁移和抗凋亡特征相关的耐药性增加。这些共同的特征导致临床治疗方案的失败。鉴定促进细胞死亡和损害细胞运动性的新型化合物是开发更有效的临床方案的合理策略。我们最近描述了小分子KCC 009（一种组织转氨酶（TG 2）抑制剂）使胶质母细胞瘤细胞对化疗敏感的能力。在目前的研究中，我们合成了一系列相关化合物，这些化合物显示出不同的促进胶质母细胞瘤细胞死亡和损害运动性的能力，而不管它们抑制TG 2的能力如何。每种化合物都有一个3-溴-4，5-二氢异恶唑组分，该组分可能与对小分子具有亲和力的蛋白质活性位点中的亲核半胱氨酸硫醇残基反应。我们的研究集中在化合物ERW 1227 B的作用上。用ERW 1227 B处理胶质母细胞瘤细胞与PI-3激酶/Akt通路的下调相关，这增强了细胞死亡;以及局灶性粘附复合物和细胞内肌动蛋白纤维的破坏相关，这损害了细胞的移动性。用ERW 1227 B处理的胶质母细胞瘤细胞的生物测定以及延时摄影显示细胞死亡和细胞运动性的快速丧失。用体内胶质母细胞瘤模型进行的小鼠研究证明了ERW 1227 B在用化疗或放疗治疗后使肿瘤细胞对细胞死亡敏感的能力。上述发现将ERW 1227 B鉴定为治疗胶质母细胞瘤的潜在新型治疗剂。
Glioblastomas display variable phenotypes that include increased drug-resistance associated with enhanced migratory and anti-apoptotic characteristics. These shared characteristics contribute to failure of clinical treatment regimens. Identification of novel compounds that promote cell death and impair cellular motility is a logical strategy to develop more effective clinical protocols. We recently described the ability of the small molecule, KCC009, a tissue transglutaminase (TG2) inhibitor, to sensitize glioblastoma cells to chemotherapy. In the current study, we synthesized a series of related compounds that show variable ability to promote cell death and impair motility in glioblastomas, irrespective of their ability to inhibit TG2. Each compound has a 3-bromo-4,5-dihydroisoxazole component that presumably reacts with nucleophilic cysteine thiol residues in the active sites of proteins that have an affinity to the small molecule. Our studies focused on the effects of the compound, ERW1227B. Treatment of glioblastoma cells with ERW1227B was associated with both down-regulation of the PI-3 kinase/Akt pathway, which enhanced cell death; as well as disruption of focal adhesive complexes and intracellular actin fibers, which impaired cellular mobility. Bioassays as well as time-lapse photography of glioblastoma cells treated with ERW1227B showed cell death and rapid loss of cellular motility. Mice studies with in vivo glioblastoma models demonstrated the ability of ERW1227B to sensitize tumor cells to cell death after treatment with either chemotherapy or radiation. The above findings identify ERW1227B as a potential novel therapeutic agent in the treatment of glioblastomas.