Format

Send to

Choose Destination
Bioorg Med Chem. 2015 Apr 1;23(7):1507-1514. doi: 10.1016/j.bmc.2015.02.003. Epub 2015 Feb 13.

Novel curcumin analogs to overcome EGFR-TKI lung adenocarcinoma drug resistance and reduce EGFR-TKI-induced GI adverse effects.

Author information

1
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA.
2
Hokkaido Pharmaceutical University, School of Pharmacy, 7-1, Katsuraoka-cho, Otaru 047-02, Japan.
3
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
4
School of Pharmacy, China Medical University, Taichung, Taiwan.
5
Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan.
6
Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan.
#
Contributed equally

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, 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.

KEYWORDS:

Curcumin; EGFR; Gastrointestinal tract; Lung adenocarcinoma; Tyrosine kinase inhibitor

PMID:
25753330
PMCID:
PMC4782611
DOI:
10.1016/j.bmc.2015.02.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center