TY - JOUR
T1 - Clinically relevant doses of candesartan inhibit growth of prostate tumor xenografts in vivo through modulation of tumor angiogenesis
AU - Alhusban, Ahmed
AU - Al-Azayzih, Ahmad
AU - Goc, Anna
AU - Gao, Fei
AU - Fagan, Susan C.
AU - Somanath, Payaningal R.
N1 - Funding Information:
Funds were provided by the University of Georgia, Wilson Pharmacy Foundation, and in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL103952] (to P.R.S.). A.A. and A.A.-A. were supported by predoctoral fellowships from Jordan University of Science and Technology. This material is the result of work supported with resources and the use of facilities at the Charlie Norwood VA Medical Center, Augusta, GA. The funders had no role in the study design, data collection, analysis, and decision to publish. Preparation of the manuscript and the contents do not represent the views of the Department of Veterans Affairs or the US Government. A.A. and A.A.-A. contributed equally to this work. dx.doi.org/10.1124/jpet.114.216382. s This article has supplemental material available at jpet.aspetjournals.org.
Funding Information:
Funds were provided by the University of Georgia, Wilson Pharmacy Foundation, and in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL103952] (to P.R.S.). A.A. and A.A.-A. were supported by predoctoral fellowships from Jordan University of Science and Technology. This material is the result of work supported with resources and the use of facilities at the Charlie Norwood VA Medical Center, Augusta, GA. The funders had no role in the study design, data collection, analysis, and decision to publish. Preparation of the manuscript and the contents do not represent the views of the Department of Veterans Affairs or the US Government.
Publisher Copyright:
© 2014, American Society for Pharmacology and Experimental Therapy. All rights reserved.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1124/jpet.114.216382
DO - 10.1124/jpet.114.216382
M3 - Article
C2 - 24990940
AN - SCOPUS:84907298153
SN - 0022-3565
VL - 350
SP - 635
EP - 645
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -