Novel EGFR-TK Inhibitor EKB-569 Inhibits Hepatocellular Carcinoma Cell Proliferation by AKT and MAPK Pathways.
10.3346/jkms.2011.26.12.1563
- Author:
Heesue KIM
1
;
Ho Yeong LIM
Author Information
1. Department of Clinical Research, Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitors (TKIs);
EKB-569;
Multi-drug Resistance;
Hepatocellular Carcinoma (HCC) Cells
- MeSH:
Aminoquinolines/*pharmacology;
Aniline Compounds/*pharmacology;
Antineoplastic Agents/*pharmacology;
Antineoplastic Combined Chemotherapy Protocols/pharmacology;
Benzenesulfonates/pharmacology;
Carcinoma, Hepatocellular/*drug therapy/pathology;
Cell Cycle Checkpoints/drug effects;
Cell Line, Tumor;
Cell Proliferation/drug effects;
Drug Resistance, Neoplasm;
Drug Synergism;
Humans;
Liver Neoplasms/drug therapy/pathology;
Mitogen-Activated Protein Kinases/*metabolism;
Phosphorylation;
Proto-Oncogene Proteins c-akt/*metabolism;
Pyridines/pharmacology;
Receptor, Epidermal Growth Factor/*antagonists & inhibitors
- From:Journal of Korean Medical Science
2011;26(12):1563-1568
- CountryRepublic of Korea
- Language:English
-
Abstract:
Epidermal growth factor receptor (EGFR)-targeted therapies have been effective in some cancers, but not in hepatocellular carcinoma (HCC). The aim of this study was to investigate the drug potential to overcome multi-drug resistance in HCC cells. Thirteen drug-sensitive HCC cells were assessed using the CCK-8 assay. G0-G1 arrest was measured by FACS. Western blot analysis was used to detect the key enzymes in both the Ras/Raf and PI3K pathways. When establishing the IC50 of HCC to several drugs, including EKB-569, sorafenib, erlotinib, gefitinib, pazopanib, and brivanib, SK-Hep1 cells treated with EKB-569 have shown the highest (72.8%-86.4%) G0-G1 arrest and decreased the phosphorylation of AKT and ERK at the protein level. We found that EKB-569 had higher efficacy in HCC, compared to first generation, reversible EGFR-TK inhibitors. Furthermore, the combination of sorafenib and EKB-569 showed a synergistic effect to inhibit proliferation of SNU-475, previously the most resistant cell to EGFR-TKIs. Therefore, novel EKB-569 in combination with sorafenib may be able to overcome HCC resistance to EGFR-TK inhibitors.
