Department of Pharmacology and Physiology and Cell-based Drug and Health Products Development Research Unit (N.S., K.P., P.C.), Faculty of Pharmaceutical Sciences and Doctor of Philosophy Program in Interdisciplinary Pharmacology, Graduate School (K.P.), Chulalongkorn University, Bangkok, Thailand; Department of Materials Engineering, Faculty of Engineering, Kasetsart University, Ladyao, Chatuchak, Bangkok, Thailand (A.L., W.W.); ivision of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University and the King Chulalongkorn Memorial Hospital, Bangkok, Thailand (C.V.); and Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand (S.L.).
Department of Pharmacology and Physiology and Cell-based Drug and Health Products Development Research Unit (N.S., K.P., P.C.), Faculty of Pharmaceutical Sciences and Doctor of Philosophy Program in Interdisciplinary Pharmacology, Graduate School (K.P.), Chulalongkorn University, Bangkok, Thailand; Department of Materials Engineering, Faculty of Engineering, Kasetsart University, Ladyao, Chatuchak, Bangkok, Thailand (A.L., W.W.); ivision of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University and the King Chulalongkorn Memorial Hospital, Bangkok, Thailand (C.V.); and Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand (S.L.)
Mol Pharmacol. 2020 Aug;98(2):130-142. doi: 10.1124/mol.120.119719. Epub 2020 Jun 2.
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, , -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 IC 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, , -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.
异常的细胞 Myc（c-Myc）是大多数人类癌症的一个常见特征，并与致癌恶性肿瘤有关。在这里，我们开发了一种新型的 c-Myc 靶向化合物， ，-双（5-乙基-2-羟基苄基）甲胺（EMD），并提供证据证明其在靶向 c-Myc 以降解人肺癌中的有效性。与化疗药物相比，EMD 通过诱导细胞凋亡，对各种人肺癌细胞系以及化疗耐药的患者来源的肺癌细胞表现出强烈的细胞毒性。EMD 对肺癌细胞的 IC 约为 60 μM。从机制上讲，EMD 消除了细胞中的 c-Myc 并引发了 caspase 依赖性凋亡级联。细胞周期蛋白 D1 chase 实验表明，EMD 倾向于将 c-Myc 的半衰期缩短约一半。与蛋白酶体抑制剂 MG132 联合处理 EMD 逆转了其针对 c-Myc 的作用，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 的泛素化并促进蛋白降解。在血液恶性 K562 细胞中还观察到 c-Myc 抑制和凋亡诱导，表明观察到的 EMD 作用具有普遍性。总之，我们确定 EMD 是一种针对致癌 c-Myc 的新型有效化合物，它可能为肺癌治疗提供新的机会。
c-Myc 的失调常与癌症进展有关。本研究在几种肺癌细胞系和耐药原代肺癌细胞中研究了一种新型化合物 ，-双（5-乙基-2-羟基苄基）甲胺（EMD）针对 c-Myc 的作用。EMD 通过泛素蛋白酶体机制诱导 c-Myc 显著降解。EMD 具有有前途的抗癌和针对 c-Myc 的活性，支持将其用于治疗由 c-Myc 驱动的癌症的潜在新方法。
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