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

Abstract. In general, oral squamous cell carcinoma (OSCC) cells are relatively resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis during culture in vitro. Here, we studied the role of phosphatidylinositol 3-kinase (PI 3-K)/Akt in survival and apoptosis of these cells. The PI 3-K inhibitors wortmannin and LY294002 markedly suppressed phosphorylation of Akt and accelerated TRAIL-mediated apoptosis in OSCC cells. Addition of TRAIL to PI 3-K inhibitor-treated cells resulted in caspase-8 activation and loss of mitochondrial membrane potential. Furthermore, inhibitors of caspase-3, -8 and -9 reduced the accelerative effect of PI 3-K inhibitors on TRAIL-mediated apoptosis. These results suggest that the pro-apoptotic effect of PI 3-K inhibitors on TRAIL-mediated apoptosis may contribute to both the extrinsic and intrinsic pathways. Although PI 3-K inhibitors did not affect expression of the TRAIL receptors DR4 and DR5, we observed a marked reduction in expression of cellular FLICE-inhibitory protein (c-FLIP), Bcl-2, cellular inhibitor of apoptosis protein-1 (cIAP-1) and X-linked IAP (XIAP), whereas Bax was up-regulated and no significant difference was observed in expression of Bcl-xL, Bak or cIAP-2. Therefore, the PI 3-K/Akt signaling pathway provides partial regulation of TRAIL-mediated apoptosis in OSCC cells via modulation of c-FLIP, Bcl-2, Bax, cIAP-1 and XIAP expression. These results suggest that PI 3-K inhibitors may represent a novel strategy for overcoming resistance to TRAILmediated apoptosis in OSCC cells.

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