Effect of combining epidermal growth factor receptor inhibitors and cisplatin on proliferation and apoptosis of oral squamous cell carcinoma cells.
Epidermal growth factor (EGF) is known to be involved in the proliferation and metastasis of squamous cell carcinoma (SCC), suggesting that the EGF receptor (EGFR) must also contribute to SCC development. In combination with conventional anti-cancer drugs, agents that block EGFR may represent an efficient means of inhibiting proliferation and inducing apoptosis in SCC cells. We investigated the effects of combining an anti-EGFR monoclonal antibody (C225) or an EGFR-selective tyrosine kinase inhibitor (AG1478) with the conventional anti-cancer drug cisplatin on the oral SCC (OSCC) cell lines NA and Ca9-22. We detected constitutive expression of EGFR on the cell membranes of both cell lines. OSCC cell proliferation was inhibited by C225, AG1478 and cisplatin in a dose-dependent manner. The combination of C225 or AG1478 with cisplatin at concentrations <IC50 synergistically inhibited cell proliferation and induced apoptosis in these cells. Furthermore, treatment with C225 or AG1478 OSCC reduced phosphorylation of EGFR and Akt, as well as Bad. EGFR inhibitors down-regulated expression levels of the anti-apoptotic proteins cellular IAP-1 (cIAP-1), X-linked IAP (XIAP), Bcl-2 and Bcl-xL, whereas those of the pro-apoptotic proteins Bax and Bak were up-regulated, and neither cIAP-2 nor survivin were affected. Therefore, EGFR inhibitors can provide partial regulation of cisplatin-mediated apoptosis in OSCC cells by modulating expression of cIAP-1, XIAP, Bcl-2, Bcl-xL, Bax and Bak. These results suggest that EGFR inhibitors may represent a novel strategy for overcoming resistance to cisplatin-mediated apoptosis via the phosphatidylinositol 3-kinase/Akt pathway.
Takaoka
Sayaka
S
Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Ota-ku, Tokyo 145-8515, Japan.
Iwase
Masayasu
M
Uchida
Makiko
M
Yoshiba
Sayaka
S
Kondo
Gen
G
Watanabe
Hitoshi
H
Ohashi
Masaru
M
Nagumo
Masao
M
Shintani
Satoru
S
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D002945:Cisplatin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000187:drug effects; D009062:Mouth Neoplasms / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects; D011799:Quinazolines; D020032:Tyrphostins / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000068818:Cetuximab; D002945:Cisplatin