A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells.
A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells.
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具有抗肿瘤活性的苯并咪唑衍生物可阻断乳腺癌细胞中的 EGFR 和 HER2 活性并上调 DR5
DOI：
10.1038/cddis.2015.25
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发表时间：
2015-03-12
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
表皮生长因子受体（EGFR）或密切相关的人表皮生长因子受体2（HER 2）的异常表达或功能可促进细胞增殖和存活，从而促进肿瘤发生。这两种蛋白质的特异性抗体和低分子量酪氨酸激酶抑制剂目前正在进行癌症治疗的临床试验。苯并咪唑衍生物具有多种生物活性，包括抗肿瘤活性。然而，5a（2-芳基苯并咪唑化合物; 2-氯-N-（2-对甲苯基-1H-苯并[d]咪唑-5-基）乙酰胺，C 16 H 14 ClN 3 O，MW 299），一种新型2-芳基苯并咪唑衍生物，对乳腺癌的抗癌机制在很大程度上是未知的。在这里，我们证明了5a通过降低EGFR和HER 2酪氨酸磷酸化并在体外和体内阻止PI 3 K/Akt和MEK/Erk途径的下游活化而有效地抑制EGFR和HER 2活性。我们还发现，5a抑制FOXO的磷酸化，并促进FOXO从细胞质易位到细胞核，导致G1期细胞周期阻滞和凋亡。此外，5a通过c-Jun N-末端激酶（JNK）介导的死亡受体5在乳腺癌细胞中的上调而有效地诱导细胞凋亡。5a的抗肿瘤活性与其他结果一致，表明5a显着减少了体内裸小鼠的肿瘤体积。对HER 2过表达的原发性乳腺癌细胞系的分析进一步证实，5a显著抑制Akt Ser 473和Bad Ser 136磷酸化并降低细胞周期蛋白D3表达。在我们的研究结果的基础上，进一步开发这种2-芳基苯并咪唑衍生物，一类新的多靶点抗癌药物，是必要的，并代表了一种新的策略，用于改善乳腺癌的治疗。
Aberrant expression or function of epidermal growth factor receptor (EGFR) or the closely related human epidermal growth factor receptor 2 (HER2) can promote cell proliferation and survival, thereby contributing to tumorigenesis. Specific antibodies and low-molecular-weight tyrosine kinase inhibitors of both proteins are currently in clinical trials for cancer treatment. Benzimidazole derivatives possess diverse biological activities, including antitumor activity. However, the anticancer mechanism of 5a (a 2-aryl benzimidazole compound; 2-chloro-N-(2-p-tolyl-1H-benzo [d] imidazol-5-yl) acetamide, C 16 H 14 ClN 3 O, MW299), a novel 2-aryl benzimidazole derivative, toward breast cancer is largely unknown. Here, we demonstrate that 5a potently inhibited both EGFR and HER2 activity by reducing EGFR and HER2 tyrosine phosphorylation and preventing downstream activation of PI3K/Akt and MEK/Erk pathways in vitro and in vivo. We also show that 5a inhibited the phosphorylation of FOXO and promoted FOXO translocation from the cytoplasm into the nucleus, resulting in the G1-phase cell cycle arrest and apoptosis. Moreover, 5a potently induced apoptosis via the c-Jun N-terminal kinase (JNK)-mediated death receptor 5 upregulation in breast cancer cells. The antitumor activity of 5a was consistent with additional results demonstrating that 5a significantly reduced tumor volume in nude mice in vivo. Analysis of the primary breast cancer cell lines with HER2 overexpression further confirmed that 5a significantly inhibited Akt Ser473 and Bad Ser136 phosphorylation and reduced cyclin D3 expression. On the basis of our findings, further development of this 2-aryl benzimidazole derivative, a new class of multitarget anticancer agents, is warranted and represents a novel strategy for improving breast cancer treatment.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
4.8
作者：
Asada, Sachie;Daitoku, Hiroaki;Fukamizu, Akiyoshi
通讯作者：
Fukamizu, Akiyoshi
影响因子：
16
作者：
Garrett, TPJ;McKern, NM;Ward, CW
通讯作者：
Ward, CW
影响因子：
3.8
作者：
Masuda, Hiroko;Zhang, Dongwei;Bartholomeusz, Chandra;Doihara, Hiroyoshi;Hortobagyi, Gabriel N.;Ueno, Naoto T.
通讯作者：
Ueno, Naoto T.
影响因子：
3.5
作者：
Kus, Canan;Ayhan-Kilcigil, Gulgun;Can-Eke, Benay
通讯作者：
Can-Eke, Benay