Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma

Gefitinib induces mitochondrial-dependent apoptosis in Saccharomyces cerevisiae

“…Changes in ∆Ψ, caspase-8 activation, caspase-3 activation and nuclear degradation, were also detected. Morevoer, gefitinib suppressed the expression of anti-apoptotic proteins, Bcl-2 and Bcl-X l , further rendering HCC cells prone to apoptosis (11). The present study on gefitinib-induced yeast apoptosis demonstrates a similar mechanism with mammalian cells, although the obvious orthologues of mammalian apoptotic regulators, namely of the Bcl-2 family, are absent in S. cerevisiae.…”

“…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. Gefitinib has been reported to inhibit the EGF-triggered pathway and the constitutive HER3-mediated Akt activation in chemoresistant cells (ovarian cancer), and to block the EGF-induced phosphorylation of ErbB-1 and mitogen-activated protein kinase (MAPK) to decrease cell proliferation in different pancreatic cancer cell lines (11,12). However, gefitinib has been reported to induce cell cycle arrest at the G1/S checkpoint in hepatocellular carcinoma, and the accumulation of cells in the G0/ G1 phase to delay human gallbladder adenocarcinoma cell growth (13,14).…”

The role of signaling pathways in the development and treatment of hepatocellular carcinoma

“…In these preclinical studies, gefitinib inhibited tumor cell growth (Matsuo et al, 2003;Okano et al, 2006), angiogenesis (Ueda et al, 2006) and intrahepatic metastasis (Matsuo et al, 2003); induced apoptosis (Hopfner et al, 2004) and cell cycle arrest (Hopfner et al, 2004); and prevented the development of HCC in cirrhotic livers (Schiffer et al, 2005). Gefitinib treatment resulted in reduced RAF/MEK/ERK, AKT and TNF-a signaling; cell cycle arrest; suppression of antiapoptotic protein expression; and stimulation of proapoptotic protein expression (Hopfner et al, 2004;Okano et al, 2006;Ueda et al, 2006). However, these encouraging preclinical results have not been matched in clinical studies.…”

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…In HCC cells, ZD1839 (Iressa; Baselga and Averbuch, 2000), which has been primarily applied in lung and breast cancer efficiently reduces tumor cell growth and induces apoptosis (Hopfner et al, 2004) and appears to inhibit metastatic activity of HCC cells (Ueno et al, 2005). Also, OSI-774 (erlotinib;Pollack et al, 1999) inhibits tumor cell growth of HCC cells based on elevated apoptosis (Huether et al, 2005b).…”