Therapeutic targeting of the endothelin a receptor in human ovarian carcinoma.

The endothelin A receptor (ET(A)R) autocrine pathway is overexpressed in many malignancies, including ovarian carcinoma. In this tumor, engagement of ET(A)R triggers tumor growth, survival, neoangiogenesis, and invasion. To evaluate whether ET(A)R represents a new target in cancer treatment, we examine in vitro and in vivo the effect of the selective ET(A)R antagonist ABT-627 (atrasentan), a small p.o. bioavailable molecule, in mono- and combination therapy with taxane. ABT-627 effectively inhibits cell proliferation, vascular endothelial growth factor (VEGF) secretion of ovarian carcinoma cell lines, and primary cultures. ET(A)R blockade also results in the sensitization to paclitaxel-induced apoptosis. In ovarian carcinoma xenografts, in which the ET-1/ET(A)R autocrine pathway is overexpressed, tumor growth was significantly inhibited in ABT-627-treated mice compared with control. The therapeutic efficacy of ABT-627 was associated with a significant reduction in microvessel density, expression of VEGF, and matrix metalloproteinase-2, and increased the percentage of apoptotic tumor cells. Combined treatment of ABT-627 with paclitaxel produced additive antitumor, apoptotic, and antiangiogenic effects. These findings demonstrate that the small molecule ABT-627 is a candidate for clinical testing as an antitumor agent in ovarian cancer patients, especially in combination with taxane therapy. Interruption of ET(A)R signaling therefore, represents, a promising therapeutic strategy in ovarian carcinoma.