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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma of Lung
  • Cell Line, Tumor
  • Curcumin / analogs & derivatives*
  • Curcumin / pharmacology
  • Curcumin / therapeutic use
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / immunology
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Gastrointestinal Diseases / chemically induced
  • Gastrointestinal Diseases / metabolism*
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Xenograft Model Antitumor Assays / methods

Substances

  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors
  • Curcumin