lisinopril and Neoplasm-Metastasis

It was reported that angiotensin II stimulates angiogenesis in vivo, and angiotensin-converting enzyme (ACE) inhibitors inhibit angiogenesis. We found that an AT1-receptor (AT1-R) antagonist, TCV-116, inhibited tumor growth, tumor-associated angiogenesis, and metastasis in a murine model. Tumor growth of Sarcoma 180 (S-180) cells and of fibrosarcoma (NFSA) cells was strongly inhibited by administration of TCV-116 in the diet at a dose of approximately 100 mg/kg/day. This reduction was accompanied with a marked reduction in tumor-associated angiogenesis. The same treatment also reduced the lung metastasis of intravenously injected Lewis lung carcinoma cells. These effects of TCV-116 were equivalent to those of the ACE inhibitor, lisinopril. In S-180 and NFSA tumor tissues, ACE and AT1a receptor (AT1a-R) mRNAs were expressed when assessed with RT-PCR. AT1b receptor and AT2 receptor, however, were not detected. Immunoreactive AT1-R was detected mainly on the neovascularized vascular endothelial cells in which expression was reduced by TCV-116 and lisinopril. These results suggested that TCV-116 inhibits the angiogenesis, growth, and metastasis of tumors highly dependent on AT1a-R blockade. Blockade of AT1a-R signaling may therefore become an effective novel strategy for tumor chemoprevention.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Antineoplastic Agents; Benzimidazoles; Biphenyl Compounds; Carcinoma, Lewis Lung; Cell Division; Drug Screening Assays, Antitumor; Fibrosarcoma; Immunohistochemistry; Lisinopril; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred ICR; Neoplasm Metastasis; Neoplasm Transplantation; Neovascularization, Pathologic; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Sarcoma 180; Sarcoma, Experimental; Signal Transduction; Tetrazoles