Antiproliferative Efficacy of Angiotensin II Receptor Blockers in Prostate Cancer

Abstract

An apparent low prevalence of cancer in hypertensive patients receiving angiotensin converting enzyme inhibitors is reported; however, the molecular mechanisms have not been elucidated. Angiotensin-II (Ang-II) is well known to be associated with hypertension, as a main peptide of the renin-angiotensin system, and its detailed molecular mechanisms have recently been elucidated. For instance, Ang-II directly activates the mitogenic signal transduction pathway through the angiotensin-II type-1 (AT1) receptor in smooth muscle cells and cardiac myocytes. Ang-II receptor blockers (ARBs), a class of antihypertensive agent, suppress signal transduction pathways mediated by growth factors such as epidermal growth factor (EGF), through the AT1 receptor. Our studies demonstrated that an ARB had the potential for antiproliferative effects and inhibition of angiogenesis in prostate cancer cells. The AT1 receptor is categorized in the guanosine phosphate binding protein-coupled receptors (GPCRs), which are viewed as critical regulators of the interactions between epithelial and stromal cells. Hence, we consider that in overcoming prostate cancer, it is very important to inhibit GPCR signaling in cancer cells by ARBs. It is unclear how prostate cancer growth changes from being hormone dependent to independent, and no effective therapy has therefore been developed. Our clinical data revealed that ARB administration decreased prostate specific antigen (PSA) and improved performance status in patients with hormone-refractory prostate cancer. This review provides an insight into the key role of Ang-II and the possibility of ARBs for molecular targeting of mitogenesis and angiogenesis in prostate cancer.

Antiproliferative activity of angiotensin II receptor blocker through cross-talk between stromal and epithelial prostate cancer cells

“…More surprisingly, there is considerable evidence that the male reproductive organs contain reninangiotensin system components, such as angiotensinogen, renin, angiotensin I -converting enzyme, and AT 1 and AT 2 receptors. O'Mahony et al suggested that the prostate gland may be the source of angiotensin II found in seminal fluid and that angiotensin II production may be regulated by androgen (39,40). Based on this accumulated evidence and our results, the prostate itself seems to be a target for angiotensin, and the prostatic renin-angiotensin system may affect the development of prostate cancer.…”

Angiotensin II Induces Oxidative Stress in Prostate Cancer

“…Recently, we have reported that angiotensin II affects the signal pathways in prostate cancer cells. Angiotensin II activates the signal transduction of mitogen-activated protein kinase and signal transducers and activators of transcription 3 and angiogenesis in prostate cancer cells (15). Also, angiotensin II facilitates the secretion of some growth factors and cytokines from prostate stromal cells, resulting in cell proliferation of prostate cancer (16).…”

Antiangiogenic Therapy in Diabetic Nephropathy

“…In addition to their intraglomerular hemodynamic effects, these drugs might diminish proteinuria and ameliorate diabetic nephropathy by other mechanisms. One interesting possibility, currently described in tumor angiogenesis, is that ACEI and ARB have antiangiogenic effects by reducing endothelial cell migration, tube formation, and Ang II-dependent productions of VEGF (11)(12)(13).…”