Angiotensin (1-7) Antagonist Diminished the Anti-Tumor Effect of Olmesartan in Tumor Cell Lines Grown In-vitro and In-vivo

Olmesartan is a selective angiotensin II type 1 receptor (AT1R) antagonist. It achieves blood pressure reduction in a dose-dependent manner through arterial vasodilation and reduced sodium retention. Secondly, olmesartan exhibits anti-angiogenic activity through inhibition of Insulin growth factor, vascular endothelial growth factor and their receptors and this effect was mediated through the Ang (1-7). The current study was to investigate the anti-tumor effect of olmesartan; first, the cytotoxic activity of olmesartan and/or Ang (1-7) antagonist on MCF-7 cell line using 3-[4, 5-dimethylthiazole-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay was explored. Then EAC solid tumor grown in vivo was employed to determine the impact of concurrent administration of an Ang (1?7) agonist or antagonist on the anti-tumor effect of olmesartan. In addition, the impact of concurrent administration of olmesartan on the cytotoxic activity of sorafenib in MCF-7 cell line or its anti-tumor effect in EAC solid tumor grown in vivo was investigated. It was observed that the cell viability was reduced by approximately 40% after sorafenib (250 μg/ml) treatment. On the other hand, olmesartan did not show any cytotoxic effect except when higher concentrations were used. IC50 value for sorafenib in MCF-7 was 250.9 μg/ml, while the IC50 value for olmesartan was 674.8 μg/ml. Ang (1-7) antagonist increased the IC50 value of olmesartan from 674.8 μg/ml to 722 μg/ml. The high cytotoxic concentration of olmesartan in combination with sorafenib failed to enhance the cytotoxicity more than the sorafenib itself. Sorafenib (30 mg/kg/day), olmesartan (3, 10 or 30 mg/kg/day) or their combination significantly (P < 0.05) reduced tumor volume and the relative tumor volume compared to EAC-Control group. Similarly, concurrent administration of the Ang (1-7) agonist with olmesartan (30 mg/kg) significantly (P < 0.05) reduced tumor volume and the relative tumor volume compared to EAC-control group or olmesartan (30 mg/kg) group. Moreover, the administration of Ang (1-7) antagonist with olmesartan reduced the anti-tumor effect of olmesartan. In conclusion, olmesartan (30 mg/kg) posses anti-tumor activity. This anti-tumor activity did not depend on the direct cytotoxic activity but might be attributed to antiangiogenic activity as proven in a previous work from our lab. The anti-tumor effect of olmesartan was, at least in part, mediated through the Ang (1-7) receptor. In addition, the present results showed that olmesartan (30 mg/kg) potentiated the anti-tumor effect of sorafenib.