학술논문
Novel c-Myc-Targeting Compound N , N -Bis (5-Ethyl-2-Hydroxybenzyl) Methylamine for Mediated c-Myc Ubiquitin-Proteasomal Degradation in Lung Cancer Cells.
Document Type
Academic Journal
Author
Sriratanasak N; 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.).; Petsri K; 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.).; Laobuthee A; 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.).; Wattanathana W; 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.).; Vinayanuwattikun C; 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.).; Luanpitpong S; 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.) suidjit@gmail.com.; Chanvorachote P; 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.) pithi.ch@gmail.com.
Source
Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE
Subject
Language
English
Abstract
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 IC 50 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.
(Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)
(Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)