ZD1839 (Gefitinib, ‘Iressa’), an epidermal growth factor receptor‐tyrosine kinase inhibitor, enhances the anti‐cancer effects of TRAIL in human esophageal squamous cell carcinoma

Abstract

The EGF (epidermal growth factor) receptor-tyrosine kinase inhibitor ZD1839 (Gefitinib, ÔIressaÕ) 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 dosedependent growth arrest at G 0 -G 1 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.

Impact of EGFR immunoexpression on STAT3 activation and association with proinflammatory/regulatory cytokine pattern in laryngeal squamous cell carcinoma

“…Investigators have confirmed the relationship between EGFR status and STAT3, and between the EGFR status and cytokine expression, such as IL-6, IL-8 or TNF· (19,20,(29)(30)(31)(32)(33)(40)(41)(42). Our results show the relationship between EGFRm and EGFR-c immunoexpression, and the mRNA amplification level, obtained by PCR for STAT3 as well as the concentrations of proinflammatory/regulatory cytokines secreted by PBMCs, especially IL-8, IFNÁ and TNF·.…”

“…In squamous cell head and neck carcinomas (HNSCC), constitutively active STAT3 has been shown to be associated with EGFR signaling and deregulated cell growth (20,21,27,28). Nevertheless, several studies have been reported, which demonstrate the interaction of proinflammatory cytokines with EGFR as well as the effects of antitumor cytokine connected with the activation of cell death program (29)(30)(31)(32)(33). It is known that TNF· is capable of activating tumor cell apoptosis through receptor clustering and the stimulation of caspases (caspase-8) (31,32).…”

Activation of Growth Factor Receptors in Esophageal Cancer—Implications for Therapy

“…Gefitinib has been shown to induce growth arrest of human esophageal cancer cell lines [46,47]. Teraishi et al [46] found no correlation between response to gefitinib and the level of EGFR expression, but in gefitinib-responsive cells they observed a dose-dependent increase in cell cycle arrest at the G 1 phase.…”

“…Teraishi et al [46] found no correlation between response to gefitinib and the level of EGFR expression, but in gefitinib-responsive cells they observed a dose-dependent increase in cell cycle arrest at the G 1 phase. Moreover, the antitumor effect of the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was enhanced by gefitinib treatment, even in cells considered to be TRAIL resistant [46]. The mechanism for this was shown to involve inhibition of EGFR-mediated Akt phosphorylation by gefitinib, leading to Bcl-xL inactivation and caspase-9 activation, thereby promoting apoptosis of cells through a mitochondrial-dependent apoptotic pathway.…”

Gefitinib induces mitochondrial-dependent apoptosis in Saccharomyces cerevisiae

“…Gefitinib has broad anti-tumour effects against various types of solid tumours, including non-small cell lung cancer, breast, ovarian cancer and head cancers (10). Although the induction of apoptosis has been considered as a major mechanism in the anti-cancer effects of gefitinib, most of these effects are EGFR-dependent.…”