Olmesartan potentiates the anti-angiogenic effect of sorafenib in mice bearing Ehrlich's ascites carcinoma: role of angiotensin (1-7).
Local renin-angiotensin systems exist in various malignant tumor tissues; this suggests that the main effector peptide, angiotensin II, could act as a key factor in tumor growth. The underlying mechanisms for the anti-angiogenic effect of angiotensin II type 1 receptor blockers need to be further evaluated. The present study was carried out to investigate the anti-angiogenic effect of olmesartan alone or in combination with sorafenib, an angiotensin (1-7) agonist or an angiotensin (1-7) antagonist in Ehrlich's ascites carcinoma-bearing mice. The tumor was induced by intradermal injection of Ehrlich's ascites carcinoma cells into mice. Tumor discs were used to evaluate the microvessel density; the serum levels of vascular endothelial growth factor (VEGF) and serum insulin-like growth factor I (IGF-I); and their intratumoral receptors, VEGF receptor-2 and IGF-I receptor, respectively. All parameters were determined following the treatment course, which lasted for 21 days post-inoculation. Monotherapy with olmesartan and its combination with sorafenib resulted in a significant reduction in microvessel density and serum levels of VEGF and IGF-I, as well as their intratumoral receptors. In addition, the combination of olmesartan (30 mg/kg) with an angiotensin (1-7) agonist reduced the microvessel density, IGF-I serum levels and the levels of its intratumoral receptor. In conclusion, olmesartan reduced the levels of the angiogenesis markers IGF-I and VEGF and down-regulated the intratumoral expression of their receptors in a dose-dependent manner, and these effects were dependent on the angiotensin (1-7) receptor. These results suggest that olmesartan is a promising adjuvant to sorafenib in the treatment of cancer.
Department of Pharmacology and Toxicology, Faculty of Pharmacy and Pharmaceutical Industries, Sinai University, Arish, Egypt.
Mohammad M
MM
Abd-Alhaseeb
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
Sawsan A
SA
Zaitone
Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Industries, Sinai University, Arish, Egypt.
Soad H
SH
Abou-El-Ela
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
Yasser M
YM
Moustafa
D000803:Angiotensin I / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010446:Peptide Fragments / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D000077157:Sorafenib; D013777:Tetrazoles / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000970:Antineoplastic Agents; D007093:Imidazoles; D010446:Peptide Fragments; D010671:Phenylurea Compounds; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D007334:Insulin-Like Growth Factor I; C437965:olmesartan; D000803:Angiotensin I; D000077157:Sorafenib; D017526:Receptor, IGF Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2; C118790:angiotensin I (1-7)