Novel c-Myc-Targeting Compound N, N-Bis (5-Ethyl-2-Hydroxybenzyl) Methylamine for Mediated c-Myc Ubiquitin-Proteasomal Degradation in Lung Cancer Cells.

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 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.

• Authors: Nicharat Sriratanasak, Korrakod Petsri, Apirat Laobuthee, Worawat Wattanathana, Chanida Vinayanuwattikun, Sudjit Luanpitpong, Pithi Chanvorachote
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 98 Issue 2 Pg. 130-142 (08 2020) ISSN: 1521-0111 [Electronic] United States
• PMID: 32487733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Antineoplastic Agents
• MYC protein, human
• Methylamines
• Proto-Oncogene Proteins c-myc
• Ubiquitin
• Proteasome Endopeptidase Complex

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Survival
• Drug Resistance, Neoplasm (drug effects)
• Humans
• K562 Cells
• Lung Neoplasms (drug therapy, metabolism)
• Methylamines (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Proteasome Endopeptidase Complex (metabolism)
• Proteolysis
• Proto-Oncogene Proteins c-myc (chemistry, drug effects, metabolism)
• Ubiquitin (metabolism)