Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and 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.
Fujita
Mamoru
M
Department of Pharmacology, Kitasato University School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan.
Hayashi
Izumi
I
Yamashina
Shohei
S
Itoman
Moritoshi
M
Majima
Masataka
M
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000096:biosynthesis / Q000235:genetics; D012510:Sarcoma 180 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; C077793:candesartan cilexetil