Clinically Relevant Doses of Candesartan Inhibit Growth of Prostate Tumor Xenografts In Vivo through Modulation of Tumor Angiogenesis

Abstract

Angiotensin II receptor type 1 blockers (ARBs), widely used antihypertensive drugs, have also been investigated for their anticancer effects. The effect of ARBs on prostate cancer in experimental models compared with meta-analysis data from clinical trials is conflicting. Whereas this discrepancy might be due to the use of supratherapeutic doses of ARBs in cellular and animal models as compared with the clinical doses used in human trials, further investigation of the effects of clinical doses of ARBs on prostate cancer in experimental models is warranted. In the current study, we sought to determine the effects of candesartan on prostate cancer cellular function in vitro and tumor growth in vivo, and characterize the underlying mechanisms. Our analysis indicated that clinically relevant doses of candesartan significantly inhibited growth of PC3 cell tumor xenografts in mice.Interestingly, the same concentrations of candesartan actually promoted prostate cancer cellular function in vitro, through a modest but significant inhibition in apoptosis. Inhibition of tumor growth by candesartan was associated with a decrease in vascular endothelial growth factor (VEGF) expression in tumors and inhibition of tumor angiogenesis, but normalization of tumor vasculature. Although candesartan did not impair PC3 cell viability, it inhibited endothelialbarrier disruption by tumor-derived factors. Furthermore, candesartan significantly inhibited expression of VEGF in PC3 and DU145 cell lines independent of angiotensin II type 2 receptor, but potentially via angiotensin II type 1 receptor inhibition. Our findings clearly demonstrate the therapeutic potential of candesartan for prostate cancer and establish a link between ARBs, VEGF expression, and prostate tumor angiogenesis.

P21 activated kinase-1 mediates transforming growth factor β1-induced prostate cancer cell epithelial to mesenchymal transition

“…The TUNEL assay for in situ detection of apoptosis was performed using the ApopTag® Fluorescein in Situ Apoptosis detection kit (Millipore, MA) as previously (Alhusban et al, 2014; Goc et al, 2012). Fixed frozen sections from prostate tumor xenografts were permeabilized in ethanol: acetic acid [2:1] mixture and labeled with fluorescein 12-dUTP using terminal deoxynucleotidyl transferase.…”

AGTR1 promoter hypermethylation in lung squamous cell carcinoma but not in lung adenocarcinoma

“…AGTR1 acts as a novel component of the renin-angiotensin system (RAS) to affect the blood pressure and heart hypertrophy (15), targeting of renin-angiotensin system (RAS) through AGTR1 blocker is associated with the resistance phenomenon in treatment of resistant breast cancers. And now the AGTR1 blocker has been applied in the clinical oncology, such as the losartan for breast cancer (22) and candesartan for prostate cancer (23). And now emerging evidences showed that AGTR1 regulates the cell proliferation during cancer development, and promotes tumor invasion, migration, metastasis and angiogenesis (24).…”

Nerve Growth Factor Facilitates the Innervation of Perivascular Nerves in Tumor-Derived Neovasculature in the Mouse Cornea

“…Furthermore, the increased production of vascular endothelial growth factor (VEGF), which plays a critical role in tumor angiogenesis, is known to contribute to the growth and development of prostate cancer [16,17] . On the other hand, the angiogenesis induced by HT1080 cells is mainly dependent on the production of VEGF [18,19] , and HT1080 cells enhance the survival, migration, and Representative confocal laser micrographic images showing the distribution of PGP 9.5-ir nerve fibers (green) and α-SMA-ir neovessels (red) in the mouse cornea treated with systemic saline or NGF for 7 days immediately ( a , b1-3 ) after or from 7 days ( c , d1-3 ) after the implantation of a gel containing DU145 cells.…”