Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and attenuates growth of murine melanoma

• Published in: Cancer chemotherapy and pharmacology Vol. 66; no. 1; pp. 79 - 87
• Main Authors: Otake, Andréia Hanada, Mattar, Ana Lucia, Freitas, Helano Carioca, Machado, Camila Maria Longo, Nonogaki, Suely, Fujihara, Clarice Kazue, Zatz, Roberto, Chammas, Roger
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-05-2010; Springer; Springer Nature B.V
• Subjects: Angiogenic Proteins - metabolism; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Antineoplastic agents; Biological and medical sciences; Cancer Research; Cell Line, Tumor; Dermatology; Female; Humans; Losartan - pharmacology; Losartan - therapeutic use; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Medical sciences; Medicine; Medicine & Public Health; Melanoma - metabolism; Melanoma - pathology; Melanoma, Experimental - blood supply; Melanoma, Experimental - drug therapy; Melanoma, Experimental - genetics; Melanoma, Experimental - metabolism; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic - drug therapy; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Receptor, Angiotensin, Type 1 - metabolism; Tumor Burden - drug effects; Tumors of the skin and soft tissue. Premalignant lesions; Angiogenesis; AT1 receptors; Angiotensin II; Losartan; Melanoma; Imidazole derivatives; Tetrazole derivatives; Growth; Peptide hormone; Non peptide compound; Octapeptide; Malignant melanoma; Inhibition; Neovascularization; Angiotensin II receptor; Rodentia; AT1 angiotensin receptor; Malignant tumor; Renin angiotensin system; Vertebrata; Mammalia; Mouse; Biphenyl derivatives; Animal; Sartan derivatives; Inhibitor; Angiotensin antagonist; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-009-1136-0

Purpose
We evaluated the involvement of angiotensin II (AngII)-dependent pathways in melanoma growth, through the pharmacological blockage of AT1 receptor by the anti-hypertensive drug losartan (LOS).
Results
We showed immunolabeling for both AngII and the AT1 receptor within the human melanoma microenvironment. Like human melanomas, we showed that murine melanomas also express the AT1 receptor. Growth of murine melanoma, both locally and at distant sites, was limited in mice treated with LOS. The reduction in tumor growth was accompanied by a twofold decrease in tumor-associated microvessel density and by a decrease in CD31 mRNA levels. While no differences were found in the VEGF expression levels in tumors from treated animals, reduction in the expression of the VEGFR1 (Flt-1) at the mRNA and protein levels was observed. We also showed downregulation of mRNA levels of both Flt-4 and its ligand, VEGF-C.
Conclusions
Together, these results show that blockage of AT1 receptor signaling may be a promising anti-tumor strategy, interfering with angiogenesis by decreasing the expression of angiogenic factor receptors.