Ovarian
carcinomas overexpress
endothelin A receptors (ET(A)R) and
epidermal growth factor (
EGF) receptor (EGFR). In these cells,
endothelin-1 (ET-1) triggers mitogenic and invasive signaling pathways that are in part mediated by EGFR transactivation. Combined targeting of ET(A)R, by the specific ET(A)R antagonist
ZD4054, and of EGFR by the EGFR inhibitor
gefitinib (
IRESSA), may offer improvements in ovarian
carcinoma treatment. In HEY and OVCA 433 ovarian
carcinoma cells, ET-1 or
EGF induced rapid activation of EGFR, p42/44
mitogen-activated protein kinase (MAPK), and AKT.
ZD4054 was able to reduce the ET-1-induced EGFR transactivation.
Gefitinib significantly inhibited
EGF- and ET-1-induced EGFR phosphorylation, but incompletely reduced the ET-1-induced activation of downstream targets.
ZD4054 plus
gefitinib resulted in a greater inhibition of EGFR, MAPK, and AKT phosphorylation, indicating the critical role of these interconnected signaling
proteins.
ZD4054 effectively inhibited cell proliferation, invasiveness, and
vascular endothelial growth factor (
VEGF) secretion. Concomitantly,
ZD4054 enhanced apoptosis and
E-cadherin promoter activity and expression. In both cell lines, the
drug combination resulted in a significant decrease in cell proliferation (65%), invasion (52%), and
VEGF production (50%), accompanied by a 2-fold increase in apoptosis. The coadministration of
ZD4054 enhanced the efficacy of
gefitinib leading to partial (82%) or complete
tumor regression on HEY ovarian
carcinoma xenografts. Antitumor effects were paralleled by biochemical and immunohistologic evidence of decreased vascularization, Ki-67,
matrix metalloproteinase-2 (MMP-2),
VEGF, MAPK and EGFR, and enhanced
E-cadherin expression. The cross-signaling between the EGFR/ET(A)R pathways provides a rationale to combine EGFR inhibitors with ET(A)R antagonists, identifying new effective therapeutic opportunities for
ovarian cancer.