title: Epigallocatechin gallate sensitizes CAL-27 human oral squamous cell             carcinoma cells to the anti-metastatic effects of gefitinib (Iressa) via synergistic             suppression of epidermal growth factor receptor and matrix metalloproteinase-2.
abstract: Human head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer-related death during the last decade due to its related metastasis and poor treatment outcomes. Gefitinib (Iressa), a tyrosine kinase inhibitor has been reported to reduce the metastatic abilities of oral cancer. Previous studies have shown that epigallocatechin gallate (EGCG), a green tea polyphenol, possesses cancer chemopreventive and anticancer activity. However, the mechanisms involved in the suppression of invasion and metastasis of human oral cancer cells following co-incubation with gefitinib and EGCG remain poorly understood. In the present study, we attempted to investigate the synergistic effects of a combined treatment of gefitinib and EGCG in CAL-27 cells in vitro and to elucidate the underlying molecular mechanisms associated with the supression of cell migration and invasion. In the present study, we found that the individual treatments or the combined treatment of gefitinib and EGCG synergistically inhibited the invasion and migration of CAL-27 cells using Transwell invasion and wound-healing scratch assays, respectively. Similarly, gefitinib in combination with EGCG synergistically attenuated enzymatic activity and the protein expression of MMP-2 in CAL-27 cells. Furthermore, individual or combined treatment with EGCG and gefitinib suppressed the protein expression of p-EGFR and the phosphorylated protein levels of ERK, JNK, p38 and AKT and displayed inhibitory effects on metastatic ability of CAL-27 cells. Combined effects of EGCG and gefitinib-altered anti-metastatic actions for related gene expression were observed using DNA microarray analysis. Importantly, EGCG sensitizes CAL-27 cells to gefitinib-suppressed phosphorylation of epidermal growth factor receptor (EGFR in vitro. Taken together, our results suggest that the synergistic suppression of the metastatic ability of CAL-27 cells after EGCG and gefitinib individual or combined treatment are mediated through mitogen-activated protein kinase (MAPK) signaling. Our novel findings provide potential insights into the mechanism involved with synergistic responses of gefitinib and EGCG against the progression of oral cancer.
authors.affiliation: Department of Dentistry, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Chang
authors.forename: Pei-Ying
authors.initials: PY
authors.lastname: Chang
authors.forename: Ming-Gene
authors.initials: MG
authors.lastname: Tu
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Lu
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Sakae
authors.initials: S
authors.lastname: Amagaya
authors.forename: Chao-Ying
authors.initials: CY
authors.lastname: Lee
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Jao
authors.forename: Michael Yuanchien
authors.initials: MY
authors.lastname: Chen
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology* / Q000556:secondary; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D002392:Catechin; C045651:epigallocatechin gallate; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D000077156:Gefitinib