Aberrant cellular Myc (c-Myc) is a common feature in the majority of human cancers and has been linked to oncogenic malignancies. Here, we developed a novel c-Myc-targeting compound, N, N-bis (5-ethyl-2-hydroxybenzyl) methylamine (EMD), and present evidence demonstrating its effectiveness in targeting c-Myc for degradation in human lung carcinoma. EMD exhibited strong cytotoxicity toward various human lung cancer cell lines, as well as chemotherapeutic-resistant patient-derived lung cancer cells, through apoptosis induction in comparison with chemotherapeutic drugs. The IC50 of EMD against lung cancer cells was approximately 60 µM. Mechanistically, EMD eliminated c-Myc in the cells and initiated caspase-dependent apoptosis cascade. Cycloheximide chase assay revealed that EMD tended to shorten the half-life of c-Myc by approximately half. The cotreatment of EMD with the proteasome inhibitor MG132 reversed its c-Myc-targeting effect, suggesting the involvement of ubiquitin-mediated proteasomal degradation in the process. We further verified that EMD strongly induced the ubiquitination of c-Myc and promoted protein degradation. c-Myc inhibition and apoptosis induction were additionally shown in hematologic malignant K562 cells, indicating the generality of the observed EMD effects. Altogether, we identified EMD as a novel potent compound targeting oncogenic c-Myc that may offer new opportunities for lung cancer treatment. SIGNIFICANCE STATEMENT: The deregulation of c-Myc is frequently associated with cancer progression. This study examined the effect of a new compound, N, N-bis (5-ethyl-2-hydroxybenzyl) methylamine (EMD), in targeting c-Myc in several lung cancer cell lines and drug-resistant primary lung cancer cells. EMD induced dramatic c-Myc degradation through a ubiquitin-proteasomal mechanism. The promising anticancer and c-Myc-targeted activities of EMD support its use in potential new approaches to treat c-Myc-driven cancer.

中文翻译：

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用于介导的c-Myc泛素-蛋白酶体降解的新型c-Myc靶向化合物N，N-双（5-乙基-2-羟基苄基）甲胺。

异常细胞Myc（c-Myc）是大多数人类癌症的常见特征，并已与致癌性恶性肿瘤联系在一起。在这里，我们开发了一种新型的靶向c-Myc的化合物N，N-双（5-乙基-2-羟基苄基）甲胺（EMD），并提供了证据证明其靶向c-Myc在人类肺癌中降解的有效性。与化疗药物相比，EMD通过诱导细胞凋亡，对各种人类肺癌细胞系以及对化疗耐药的患者来源的肺癌细胞具有较强的细胞毒性。EMD对肺癌细胞的IC50约为60 µM。从机理上讲，EMD消除了细胞中的c-Myc并启动了caspase依赖性细胞凋亡级联反应。环己酰亚胺的追赶试验表明，EMD倾向于将c-Myc的半衰期缩短大约一半。EMD与蛋白酶体抑制剂MG132的共处理逆转了其c-Myc靶向作用，表明该过程涉及泛素介导的蛋白酶体降解。我们进一步验证了EMD强烈诱导c-Myc的泛素化并促进了蛋白质降解。在血液恶性K562细胞中还显示了c-Myc抑制和凋亡诱导作用，表明观察到的EMD效应具有普遍性。总而言之，我们将EMD确定为靶向致癌c-Myc的新型有效化合物，可能为肺癌治疗提供新的机会。意义声明：c-Myc的失调通常与癌症的进展有关。这项研究研究了一种新化合物N，N-双（5-乙基-2-羟基苄基）甲胺（EMD）的作用，在几种肺癌细胞系和耐药原发性肺癌细胞中靶向c-Myc的作用。EMD通过泛素-蛋白酶体机制诱导c-Myc急剧降解。EMD有希望的抗癌和c-Myc靶向活性支持其在治疗c-Myc驱动的癌症的潜在新方法中的应用。