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.
Laboratories of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, 00158 Rome, Italy.
Laura
L
Rosanò
Francesca
F
Spinella
Debora
D
Salani
Valeriana
V
Di Castro
Aldo
A
Venuti
Maria Rita
MR
Nicotra
Pier Giorgio
PG
Natali
Anna
A
Bagnato
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077868:Atrasentan; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D065128:Endothelin Receptor Antagonists; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008222:Lymphokines / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D065128:Endothelin Receptor Antagonists; D006131:Growth Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017239:Paclitaxel; D000077868:Atrasentan