The autocrine
endothelin (ET)-1/
endothelin A receptor (ET(A)R) pathway is an important regulator of several processes involved in
ovarian cancer progression, and its overexpression is associated with aggressive disease. These features have led to the proposal of the ET(A)R receptor as a potential target for improving
ovarian cancer treatment. In this study, we evaluated in vitro and in vivo the effects of
ZD4054, an orally active antagonist that specifically binds ET(A)R, as monotherapy, and in combination with
paclitaxel. In the human
ovarian cancer ET(A)R-positive cell lines HEY, OVCA 433, SKOV-3, and A-2780,
ZD4054 effectively inhibited the basal and ET-1-induced cell proliferation, associated with the inhibition of AKT and p42/44MAPK phosphorylation, and with increased apoptosis, through the inhibition of bcl-2 and activation of
caspase-3 and
poly(ADP-ribose) polymerase proteins.
ZD4054 treatment also resulted in a reduction of ET(A)R-driven angiogenesis and invasive mediators, such as
vascular endothelial growth factor,
cyclooxygenase-1/2, and
matrix metalloproteinase (
MMP). The combination of
ZD4054 and
paclitaxel led to the potentiation of all these effects, indicating that
ZD4054, by blocking the ET(A)R-dependent proliferative, invasive, and antiapoptotic signals, can enhance sensitivity to
paclitaxel. In HEY
ovarian cancer xenografts,
ZD4054 significantly inhibited
tumor growth to the same degree as
paclitaxel. Furthermore, ZD4054-dependent
tumor growth inhibition was associated with a reduction in proliferation index, microvessel density, and MMP-2 expression. Interestingly, the combination of
ZD4054 and
paclitaxel produced additive antitumor effects, with 40% of mice remaining
tumor-free, supporting a rationale for the clinical use of
ZD4054 as monotherapy or in combination with cytotoxic drugs.