In human ovarian
carcinoma, the
endothelin-1 (ET-1) /
endothelin A receptor (ETAR) axis is overexpressed, correlating with
tumor grade. Moreover, ETAR activation by ET-1 affects cell proliferation, survival, angiogenesis, and invasion. ETAR blockade with
zibotentan (
ZD4054), a specific ETAR antagonist, significantly inhibits
ovarian cancer growth in vitro and in vivo, underscoring the relevance of this pathway as a target for
cancer therapy. Since clinical trial results have defined the combination of
platinum and
taxane as the standard of care in the management of
ovarian cancer, here we explored the therapeutic efficacy of the integration of
zibotentan with cytotoxic drugs having different modes of action. We found that the combination of
zibotentan with cisplatinum as well as
zibotentan with
paclitaxel was more effective at inhibiting
ovarian cancer HEY cell proliferation induced by endogenous ET-1 than were the single agents alone. However, a significantly enhanced efficacy was observed when we combined
zibotentan, cisplatinum, and
paclitaxel. Accordingly, in HEY xenografts the coadministration of
zibotentan with cisplatinum enhanced the efficacy of the cytotoxic
drug alone in controlling
tumor growth, associated with reduction in proliferation index and microvessel density. Remarkably, the combination of
zibotentan with both cisplatinum and
paclitaxel was very effective in inhibiting
tumor growth, neovascularization, and cell proliferation, representing a preclinical endpoint to guide combination
therapy in clinical trials.