National Brain Research Centre, Manesar, Gurgaon, Haryana, India.
Mol Carcinog. 2013 Dec;52(12):970-82. doi: 10.1002/mc.21938. Epub 2012 Jun 29.
The importance of aberrant EGFR signaling in glioblastoma progression and the promise of EGFR-specific therapies, prompted us to determine the efficacy of novel EGFR inhibitor BIBU-1361 [(3-chloro-4-fluoro-phenyl)-[6-(4-diethylaminomethyl-piperidin-1-yl)-pyrimido [5,4-d]pyrimidin-4-yl]-amine] in affecting glioma survival. BIBU induced apoptosis in a caspase-dependent manner and induced cell cycle arrest in glioma cells. Apoptosis was accompanied by decreased EGFR levels and its increased distribution towards caveolin rich lipid raft microdomains. BIBU inhibited pro-survival pathways Akt/mTOR and gp130/JAK/STAT3; and decreased levels of pro-inflammatory cytokine IL-6. BIBU caused increased LC3-I to LC3-II conversion and triggered the internalization of EGFR within vacuoles along with its increased co-localization with LC3-II. BIBU caused accumulation of p62 and increased levels of cleaved forms of Beclin-1 in all the cell lines tested. Importantly, BIBU failed to initiate execution of autophagy as pharmacological inhibition of autophagy with 3-Methyladenine or Bafilomycin failed to rescue BIBU mediated death. The ability of BIBU to abrogate Akt and STAT3 activation, induce apoptosis and prevent execution of autophagy warrants its investigation as a potent anti-glioma target.
异常 EGFR 信号在胶质母细胞瘤进展中的重要性和 EGFR 特异性治疗的前景，促使我们确定新型 EGFR 抑制剂 BIBU-1361[(3-氯-4-氟苯基)-[6-(4-二乙基氨基甲基-哌啶-1-基)-嘧啶并[5,4-d]嘧啶-4-基]-胺]在影响胶质瘤存活方面的疗效。BIBU 以半胱天冬酶依赖的方式诱导细胞凋亡，并诱导神经胶质瘤细胞周期停滞。凋亡伴随着 EGFR 水平的降低及其向富含小窝蛋白的脂筏微区室的分布增加。BIBU 抑制了促生存途径 Akt/mTOR 和 gp130/JAK/STAT3；并降低了促炎细胞因子 IL-6 的水平。BIBU 引起 LC3-I 向 LC3-II 的转化增加，并触发 EGFR 在内含体中的内化，同时增加与 LC3-II 的共定位。BIBU 导致 p62 积累，并增加所有测试细胞系中 Beclin-1 的裂解形式的水平。重要的是，BIBU 未能启动自噬的执行，因为用 3-甲基腺嘌呤或巴弗洛霉素进行自噬的药理学抑制未能挽救 BIBU 介导的死亡。BIBU 能够废除 Akt 和 STAT3 的激活、诱导细胞凋亡和防止自噬的执行，这使其成为一种有效的抗神经胶质瘤靶点，值得进一步研究。
