Effect of combining epidermal growth factor receptor inhibitors and cisplatin on proliferation and apoptosis of oral squamous cell carcinoma cells

Sayaka Takaoka, Masayasu Iwase, Makiko Uchida, Sayaka Yoshiba, Gen Kondo, Hitoshi Watanabe, Masaru Ohashi, Masao Nagumo, Satoru Shintani
International Journal of Oncology 2007, 30 (6): 1469-76
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.

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