https://scholars.lib.ntu.edu.tw/handle/123456789/191077
Title: | Novel curcumin analogs to overcome EGFR-TKI lung adenocarcinoma drug resistance and reduce EGFR-TKI-induced GI adverse effects | Authors: | Wada, Koji Lee, Jen-Yi Hung, Hsin-Yi Shi, Qian Lin, Li Zhao, Yu Goto, Masuo PAN-CHYR YANG Kuo, Sheng-Chu HUEI-WEN CHEN Lee, Kuo-Hsiung |
Keywords: | Curcumin;EGFR;Gastrointestinal tract;Lung adenocarcinoma;Tyrosine kinase inhibitor | Issue Date: | 2015 | Journal Volume: | 23 | Journal Issue: | 7 | Start page/Pages: | 1507-1514 | Source: | Bioorg. Med. Chem. | Abstract: | 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, 815, 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. (C) 2015 Elsevier Ltd. All rights reserved. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/279062 | DOI: | 10.1016/j.bmc.2015.02.003 | SDG/Keyword: | curcumin; curcumin derivative; dimethoxycurcumin; epidermal growth factor receptor; gefitinib; unclassified drug; curcumin; EGFR protein, human; epidermal growth factor receptor; protein kinase inhibitor; Article; cancer cell line; cell proliferation; controlled study; digestive system injury; down regulation; drug determination; drug synthesis; human; human cell; lung adenocarcinoma; physical parameters; protein degradation; protein expression; protein phosphorylation; structure activity relation; adenocarcinoma; analogs and derivatives; antagonists and inhibitors; chemically induced; chemistry; drug effects; drug resistance; drug screening; gastrointestinal disease; immunology; Lung Neoplasms; metabolism; procedures; tumor cell line; Adenocarcinoma; Cell Line, Tumor; Curcumin; Drug Resistance, Neoplasm; Gastrointestinal Diseases; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Receptor, Epidermal Growth Factor; Xenograft Model Antitumor Assays |
Appears in Collections: | 醫學系 |
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