Novel curcumin analogs to overcome EGFR-TKI lung adenocarcinoma drug resistance and reduce EGFR-TKI-induced GI adverse effects
Resource
Bioorg. Med. Chem., 23(7), 1507-1514
Journal
Bioorg. Med. Chem.
Journal Volume
23
Journal Issue
7
Pages
1507-1514
Date Issued
2015
Date
2015
Author(s)
Wada, Koji
Lee, Jen-Yi
Hung, Hsin-Yi
Shi, Qian
Lin, Li
Zhao, Yu
Goto, Masuo
Kuo, Sheng-Chu
Lee, Kuo-Hsiung
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.
Subjects
Curcumin
EGFR
Gastrointestinal tract
Lung adenocarcinoma
Tyrosine kinase inhibitor
SDGs
Other Subjects
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