...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemical Pharmacology >Inhibition of epidermal growth factor receptor-overexpressing cancer cells by camptothecin, 20-(N,N-diethyl) glycinate.
【24h】

Inhibition of epidermal growth factor receptor-overexpressing cancer cells by camptothecin, 20-(N,N-diethyl) glycinate.

机译：喜树碱20-（N，N-二乙基）甘氨酸盐抑制表皮生长因子受体过表达的癌细胞。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The epidermal growth factor receptor (EGFR) represents a prognostic marker for short survival of patients and therapy resistance of tumors. Despite clinical usefulness of EGFR tyrosine kinase inhibitors, resistance can develop. Therefore, there is an urgent need for novel EGFR inhibitors. Camptothecins have been characterized as inhibitors of DNA topoisomerase I (TOP1), although a correlation between TOP1 expression and activity is not well established in clinical biopsies. Hence, other targets may also be relevant. By molecular docking, we found that camptothecin 20-N,N-glycinate (CPTg) and camptothecin (CPT) bind to the same pharmacophore at EGFR as erlotinib, albeit to partly different amino acids. To validate the in silico results, CPT and CPTg were evaluated for their cytotoxic activity and downstream signaling mechanisms in U87MG glioblastoma cell lines transduced with different expression vectors for EGFR. All transduced cell lines were more susceptible to CPTg or CPT than the non-transduced cells, indicating a preferential activity towards EGFR-expressing tumor cells. Microarray-based mRNA hybridizations were performed in treated a non-treated cell lines. Subsets of genes were commonly regulated between the cell lines. By pathway analyses, we ranked canonical pathways according to differential gene expression after drug treatment. The pathways for G2/M DNA damage checkpoint regulation, aryl hydrocarbon receptor signaling, and xenobiotic metabolism and endoplasmatic reticulum stress were top ranked. In conclusion, binding of CPTg and CPT to the erlotinib pharmacophore and preferential cytotoxicity towards EGFR-overexpressing cells indicate susceptibility towards erlotinib-resistant tumors. Multiple mechanisms may account for cytotoxicity of these camptothecins.
机译：表皮生长因子受体（EGFR）代表了患者生存期短和肿瘤治疗耐药的预后指标。尽管EGFR酪氨酸激酶抑制剂在临床上有用，但仍会产生耐药性。因此，迫切需要新型EGFR抑制剂。喜树碱已被表征为DNA拓扑异构酶I（TOP1）的抑制剂，尽管在临床活检中并未很好地确定TOP1表达与活性之间的相关性。因此，其他目标也可能是相关的。通过分子对接，我们发现喜树碱20-N，N-甘氨酸盐（CPTg）和喜树碱（CPT）与埃罗替尼在EGFR上结合到相同的药效基团，尽管部分氨基酸不同。为了验证计算机模拟结果，评估了CPT和CPTg在用不同EGFR表达载体转导的U87MG胶质母细胞瘤细胞系中的细胞毒活性和下游信号传导机制。所有转导的细胞系比未转导的细胞对CPTg或CPT更敏感，表明对表达EGFR的肿瘤细胞具有优先活性。在未处理的细胞系中进行基于微阵列的mRNA杂交。通常在细胞系之间调节基因的亚集。通过途径分析，我们根据药物治疗后的差异基因表达对典型途径进行了排名。 G2 / M DNA损伤检查点调节，芳基烃受体信号转导，异种生物代谢和内质网应激的途径均位居榜首。总之，CPTg和CPT与厄洛替尼药效团的结合以及对EGFR过表达细胞的优先细胞毒性表明对厄洛替尼耐药性肿瘤易感。多种机制可能解释了这些喜树碱的细胞毒性。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号