TY - JOUR
T1 - Inhibition of the renin-angiotensin system downregulates tissue factor and vascular endothelial growth factor in human breast carcinoma cells
AU - Napoleone, Emanuela
AU - Cutrone, Antonella
AU - Cugino, Daniela
AU - Amore, Concetta
AU - Di Santo, Angelomaria
AU - Iacoviello, Licia
AU - De Gaetano, Giovanni
AU - Donati, Maria Benedetta
AU - Lorenzet, Roberto
PY - 2012/6
Y1 - 2012/6
N2 - Introduction: The renin-angiotensin system (RAS) promotes angiogenesis and growth of neoplastic cells. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor AT1 blockers may protect against cancer. Tissue factor (TF), for its involvement in tumor growth, angiogenesis, and metastasis is considered a hallmark of cancer progression. In this study we evaluated whether RAS blockade modulates TF constitutive expression by the metastatic breast carcinoma MDA-MB-231 cell line. Materials and Methods: Cell TF activity was assessed by one stage clotting time, TF and VEGF antigens and mRNA levels by ELISA and RT-PCR, respectively. AT1 was detected by flow-cytometry and angiotensin-II levels by EIA. Results: Captopril reduced in a concentration-dependent way both the strong constitutive TF activity (983.2 ± 55.2 vs. 686.7 ± 135.1 U/5 × 105 cells with 10 μg/ml captopril) and antigen (32.3 ± 5.9 vs. 13.2 ± 6.6 ng/ml) in MDA-MB-231. Similar results were observed with enalapril. AT1 was present on cell membrane and losartan, a competitive inhibitor of AT1, reduced TF expression to a degree similar as that exerted by ACE inhibitors. Moreover, captopril and losartan downregulated the constitutive mRNA TF expression by ~ 35%. Similar results were observed with anti-AT1 and angiotensin II antibodies. In addition, the constitutive VEGF antigen and mRNA levels were reduced in the presence of captopril or losartan, and an anti-VEGF antibody downregulated cell TF activity by ~ 40%. Conclusions: These results could, at least in part, contribute to the discussion about the possible effects of ACE inhibitors and AT1 receptor antagonists in malignancy, and offer new clues to support their use for tumor control.
AB - Introduction: The renin-angiotensin system (RAS) promotes angiogenesis and growth of neoplastic cells. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor AT1 blockers may protect against cancer. Tissue factor (TF), for its involvement in tumor growth, angiogenesis, and metastasis is considered a hallmark of cancer progression. In this study we evaluated whether RAS blockade modulates TF constitutive expression by the metastatic breast carcinoma MDA-MB-231 cell line. Materials and Methods: Cell TF activity was assessed by one stage clotting time, TF and VEGF antigens and mRNA levels by ELISA and RT-PCR, respectively. AT1 was detected by flow-cytometry and angiotensin-II levels by EIA. Results: Captopril reduced in a concentration-dependent way both the strong constitutive TF activity (983.2 ± 55.2 vs. 686.7 ± 135.1 U/5 × 105 cells with 10 μg/ml captopril) and antigen (32.3 ± 5.9 vs. 13.2 ± 6.6 ng/ml) in MDA-MB-231. Similar results were observed with enalapril. AT1 was present on cell membrane and losartan, a competitive inhibitor of AT1, reduced TF expression to a degree similar as that exerted by ACE inhibitors. Moreover, captopril and losartan downregulated the constitutive mRNA TF expression by ~ 35%. Similar results were observed with anti-AT1 and angiotensin II antibodies. In addition, the constitutive VEGF antigen and mRNA levels were reduced in the presence of captopril or losartan, and an anti-VEGF antibody downregulated cell TF activity by ~ 40%. Conclusions: These results could, at least in part, contribute to the discussion about the possible effects of ACE inhibitors and AT1 receptor antagonists in malignancy, and offer new clues to support their use for tumor control.
KW - Cancer cells
KW - RAS inhibitors
KW - Tissue factor
KW - Vascular endothelial growth factor
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U2 - 10.1016/j.thromres.2011.11.047
DO - 10.1016/j.thromres.2011.11.047
M3 - Article
C2 - 22188725
AN - SCOPUS:84857788981
VL - 129
SP - 736
EP - 742
JO - Thrombosis Research
JF - Thrombosis Research
SN - 0049-3848
IS - 6
ER -