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.