Novel curcumin analogs to overcome EGFR–TKI lung adenocarcinoma drug resistance and reduce EGFR–TKI-induced GI adverse effects
| Autor: | Jen Yi Lee, Sheng-Chu Kuo, Hsin Yi Hung, Li Lin, Qian Shi, Hui-Wen Chen, Yu Zhao, Koji Wada, Pan-Chyr Yang, Masuo Goto, Kuo Hsiung Lee |
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| Rok vydání: | 2015 |
| Předmět: |
Curcumin
Lung Neoplasms Gastrointestinal Diseases medicine.drug_class Clinical Biochemistry Pharmaceutical Science Adenocarcinoma of Lung Adenocarcinoma Pharmacology Biochemistry Article Tyrosine-kinase inhibitor T790M chemistry.chemical_compound Cell Line Tumor Drug Discovery medicine Humans Epidermal growth factor receptor Protein Kinase Inhibitors Molecular Biology Gastrointestinal tract biology Chemistry Organic Chemistry medicine.disease Xenograft Model Antitumor Assays respiratory tract diseases ErbB Receptors Drug Resistance Neoplasm Cell culture biology.protein Molecular Medicine Phosphorylation |
| Zdroj: | Bioorganic & Medicinal Chemistry. 23:1507-1514 |
| ISSN: | 0968-0896 |
| Popis: | Curcumin (1) down-regulates the expression as well as phosphorylation of epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells expressing gefitinib-resistant EGFR. Thirty-seven newly synthesized curcumin analogues including dimethoxycurcumin (2, DMC) were evaluated for their effects on EGFR expression as well as phosphorylation in two gefitinib-resistant lung adenocarcinoma cell lines, CL1-5 (EGFR(wt)) and H1975 (EGFR(L858R+T790M)). Based on the identified structure-activity relationships, methoxy substitution at C-3', C-4', or both positions favored inhibitory activity (compounds 1, 2, 5, 8-15, 17, 36), while compounds with more polar substituents were generally less active in both cell lines. Compound 36 with a fluorine substituent at C-6' and its protonated counterpart 2 did not lose activity, suggesting halogen tolerance. In addition, a conjugated linker was essential for activity. Among all evaluated curcumin derivatives, compound 2 showed the best inhibitory effects on both wild-type and mutant EGFR by efficiently inducing gefitinib-insensitive EGFR degradation. Compound 23 also reduced gefitinib-induced gastrointestinal damage in the non-transformed intestinal epithelial cell line IEC-18. |
| Databáze: | OpenAIRE |
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