Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: a possibility of tyrosine kinase inhibitor of growth factor.
Angiotensin II (A-II) receptor (AT(1) receptor) blockers (ARB) are a class of antihypertensive agent. It is known that they suppress signal transduction pathways mediated by growth factors [e.g., epidermal growth factor (EGF)] through the AT(1) receptor in vascular endothelial cells. In the present study, we demonstrated that A-II activates the cell proliferation of prostate cancer as well as EGF. In addition, we showed that A-II induces the phosphorylations of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) in prostate cancer cells. In contrast, ARB was shown to inhibit the proliferation of prostate cancer cells stimulated with EGF or A-II, the mechanism of which is through the suppression of MAPK or STAT3 phosphorylation by ARB. Oral administration of ARB to nude mice inhibited the growth of prostate cancer xenografts in both androgen-dependent and androgen-independent cells in a dose-dependent manner. Microvessel density was reduced in xenografts treated with ARB, which means ARB inhibits the vascularization of xenografts. Expression of AT(1) receptor mRNA was examined by reverse transcription-PCR using 10 pairs of human prostate cancer and normal prostate tissues. AT(1) receptor expression in human prostate cancer tissue was higher (9 of 10 cases) than that in normal prostate tissue. These results suggest the possibility that ARB is a novel therapeutic class of agents for prostate cancer, especially hormone-independent tumors.