ZD1839 (Gefitinib, 'Iressa'), an epidermal growth factor receptor-tyrosine kinase inhibitor, enhances the anti-cancer effects of TRAIL in human esophageal squamous cell carcinoma.
The EGF (epidermal growth factor) receptor-tyrosine kinase inhibitor ZD1839 (Gefitinib, 'Iressa') blocks the cell signaling pathways involved in cell proliferation, survival, and angiogenesis in various cancer cells. TNF-related death apoptosis inducing ligand (TRAIL) acts as an anticancer agent. We investigated the antitumor effects of ZD1839 alone or in combination with TRAIL against human esophageal squamous cell cancer (ESCC) lines. Although all ESCC cells expressed EGF receptor at a protein level, the effect of ZD1839 on cell growth did not correlate with the level of EGFR expression and phosphorylation of EGF receptor protein in ESCC lines. ZD1839 caused a dose-dependent growth arrest at G0-G1 phase associated with increased p27 expression. As TE8 cells are resistant to TRAIL, we tested whether ZD1839 combined with TRAIL induced apoptosis of TE8 cells via the inhibition of EGF receptor signaling by ZD1839. ZD1839 inhibited the phosphorylation of Akt, and enhanced TRAIL-induced apoptosis via activation of caspase-3 and caspase-9, and inactivation of Bcl-xL. Our results indicated that ZD1839 has anti-cancer properties against human esophageal cancer cells. ZD1839 also augmented the anti-cancer activity of TRAIL, even in TRAIL-resistant tumors. These results suggest that treatment with ZD1839 and TRAIL may have potential in the treatment of ESCC patients.
Teraishi
Fuminori
F
Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan.
Kagawa
Shunsuke
S
Watanabe
Takanori
T
Tango
Yasuhisa
Y
Kawashima
Takeshi
T
Umeoka
Tatsuo
T
Nisizaki
Masahiko
M
Tanaka
Noriaki
N
Fujiwara
Toshiyoshi
T
D051017:Apoptosis Regulatory Proteins; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016193:G1 Phase; D000077156:Gefitinib; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D000077156:Gefitinib; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; C505653:TNFSF10 protein, human; C494918:AKT1 protein, human