TY - JOUR
T1 - Combination therapy of zibotentan with cisplatinum and paclitaxel is an effective regimen for epithelial ovarian cancer
AU - Rosanò, Laura
AU - Cianfrocca, Roberta
AU - Spinella, Francesca
AU - Di Castro, Valeriana
AU - Natali, Pier Giorgio
AU - Bagnato, Anna
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
KW - Combination therapy
KW - ET-1
KW - ET receptor
KW - Ovarian cancer
KW - Zibotentan
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U2 - 10.1139/Y10-053
DO - 10.1139/Y10-053
M3 - Article
C2 - 20628434
AN - SCOPUS:79952276287
VL - 88
SP - 676
EP - 681
JO - Canadian Journal of Physiology and Pharmacology
JF - Canadian Journal of Physiology and Pharmacology
SN - 0008-4212
IS - 6
ER -