New substituted quinoxalines inhibit triple-negative breast cancer by specifically downregulating the c-MYC transcription
New substituted quinoxalines inhibit triple-negative breast cancer by specifically downregulating the c-MYC transcription
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新的喹喔啉取代物通过特异性下调 c-MYC 转录来抑制三阴性乳腺癌
DOI：
10.1093/nar/gkz835
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发表时间：
2019-11-18
影响因子：
14.9
通讯作者：
Jin, Guangyi
中科院分区：
文献类型：
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作者：
Hu, Ming-Hao;Wu, Tian-Ying;Jin, Guangyi
传统化疗仍然是三阴性乳腺癌(TNBC)的主要治疗选择。然而，目前的化疗药物对TNBC的作用有限，往往会导致严重的副作用和耐药性。因此，迫切需要更有效的治疗选择。由于c-myc癌基因在TNBC的发病过程中高度表达，抑制c-myc的表达将是一种可供选择的抗TNBC策略。在这项研究中，我们设计并合成了一系列针对c-myc启动子G-四链(G4)的喹恶啉类似物，G4被认为是c-myc转录的抑制因子。其中，一种二氟取代喹恶啉QN-1被确定为最有希望的G4稳定配体，与其他G4S相比，它对c-myc G4具有较高的选择性，这与许多已报道的配体不同。细胞内研究表明，QN-1诱导细胞周期停滞和凋亡，抑制转移和抑制TNBC细胞生长，主要是由于G4依赖的机制下调c-myc转录。值得注意的是，QN-1对c-myc的抑制作用明显大于其他G4驱动的基因。与正常细胞相比，高表达c-myc的癌细胞对QN-1更敏感。此外，QN-1有效地抑制了TNBC小鼠模型中的肿瘤生长。因此，这项工作为治疗TNBC提供了一种替代策略。
Conventional chemotherapy remains the primary treatment option for triple-negative breast cancer (TNBC). However, the current chemotherapeutic drugs have limited effects on TNBC, and often lead to serious side effects as well as drug resistance. Thus, more effective therapeutic options are sorely needed. As c-MYC oncogene is highly expressed during TNBC pathogenesis, inhibiting c-MYC expression would be an alternative anti-TNBC strategy. In this study, we designed and synthesized a serial of quinoxaline analogs that target c-MYC promoter G-quadruplex (G4), which is believed to be a repressor of c-MYC transcription. Among them, a difluoro-substituted quinoxaline QN-1 was identified as the most promising G4-stabilizing ligand with high selectivity to c-MYC G4 over other G4s, which is distinguished from many other reported ligands. Intracellular studies indicated that QN-1 induced cell cycle arrest and apoptosis, repressed metastasis and inhibited TNBC cell growth, primarily due to the downregulation of c-MYC transcription by a G4-dependent mechanism. Notably, inhibition by QN-1 was significantly greater for c-MYC than other G4-driven genes. Cancer cells with c-MYC overexpression were more sensitive to QN-1, relative to normal cells. Furthermore, QN-1 effectively suppressed tumor growth in a TNBC mouse model. Accordingly, this work provides an alternative strategy for treating TNBC.