Preclinical anticancer activity of the specific endothelin A receptor antagonist ZD4054

Endothelins are a family of small peptides (ET-1, ET-2, and ET-3) that mediate various physiological processes of mitogenesis, repair, and tissue differentiation by binding to endothelin A (ETA) and endothelin B (ETB) cell surface receptors. Activation of the ETA receptor by ET-1 has emerged as an important factor promoting tumor cell proliferation, survival, angiogenesis, migration, invasion, and metastasis in several tumor types including prostate, ovary, colon, cervix, breast, and lung. As activation of the ETB receptor has an opposing effect, inducing cell death by apoptosis, a rationale exists for specific antagonism of the ETA receptor as a treatment strategy for cancer. ZD4054 is a specific ETA receptor antagonist currently being evaluated in hormone-resistant prostate cancer in phase III clinical trials. In vitro, ZD4054 reversed ET-1-mediated inhibition of apoptosis in serum-deprived rat A10 and human VLTR-16 cells in a concentration-dependent manner. ZD4054 inhibited ET-1-mediated survival signaling pathways and decreased proliferation in ovarian OVCA 433 and HEY cells and in prostate PPC-1 and LAPC-4 cells. In A673 rhabdomyosarcoma cells, ET-1-induced phosphorylation of FAK, FAK, and paxillin was reversed with ZD4054, inhibiting the invasive phenotype mediated by these adhesion factors. In vivo, ZD4054 led to a significant reduction in tumor growth in animals bearing ovarian tumor xenografts, and significantly inhibited tumor angiogenesis. Pretreatment with ZD4054 also significantly delayed the onset of metastatic events after intracardiac injection of bladder TSU-Pr1-B1 cells in mice. These preclinical data show the potential anticancer effects of the specific blockade of the ETA receptor with ZD4054, supporting a program of clinical investigation.