title: 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 endothelial-barrier 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.
authors.affiliation: Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy and the Charlie Norwood VA Medical Center, Augusta, Georgia (A.A., A.A.-A., A.G., F.G., S.C.F., P.R.S.); Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan (A.A.); and Departments of Neurology (S.C.F.), Medicine (P.R.S.), Cancer Center (P.R.S.), and Vascular Biology Center (P.R.S.), Georgia Regents University, Augusta, Georgia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Alhusban
authors.affiliation: Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy and the Charlie Norwood VA Medical Center, Augusta, Georgia (A.A., A.A.-A., A.G., F.G., S.C.F., P.R.S.); Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan (A.A.); and Departments of Neurology (S.C.F.), Medicine (P.R.S.), Cancer Center (P.R.S.), and Vascular Biology Center (P.R.S.), Georgia Regents University, Augusta, Georgia.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Azayzih
authors.affiliation: Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy and the Charlie Norwood VA Medical Center, Augusta, Georgia (A.A., A.A.-A., A.G., F.G., S.C.F., P.R.S.); Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan (A.A.); and Departments of Neurology (S.C.F.), Medicine (P.R.S.), Cancer Center (P.R.S.), and Vascular Biology Center (P.R.S.), Georgia Regents University, Augusta, Georgia.
authors.forename: Anna
authors.initials: A
authors.lastname: Goc
authors.affiliation: Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy and the Charlie Norwood VA Medical Center, Augusta, Georgia (A.A., A.A.-A., A.G., F.G., S.C.F., P.R.S.); Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan (A.A.); and Departments of Neurology (S.C.F.), Medicine (P.R.S.), Cancer Center (P.R.S.), and Vascular Biology Center (P.R.S.), Georgia Regents University, Augusta, Georgia.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy and the Charlie Norwood VA Medical Center, Augusta, Georgia (A.A., A.A.-A., A.G., F.G., S.C.F., P.R.S.); Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan (A.A.); and Departments of Neurology (S.C.F.), Medicine (P.R.S.), Cancer Center (P.R.S.), and Vascular Biology Center (P.R.S.), Georgia Regents University, Augusta, Georgia.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Fagan
authors.affiliation: Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy and the Charlie Norwood VA Medical Center, Augusta, Georgia (A.A., A.A.-A., A.G., F.G., S.C.F., P.R.S.); Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan (A.A.); and Departments of Neurology (S.C.F.), Medicine (P.R.S.), Cancer Center (P.R.S.), and Vascular Biology Center (P.R.S.), Georgia Regents University, Augusta, Georgia sshenoy@gru.edu.
authors.forename: Payaningal R
authors.initials: PR
authors.lastname: Somanath
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013777:Tetrazoles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; C081643:candesartan