Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis

Biochem Biophys Res Commun. 2002 Jun 7;294(2):441-7. doi: 10.1016/S0006-291X(02)00496-5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin Receptor Antagonists*
  • Animals
  • Antihypertensive Agents / pharmacology
  • Antineoplastic Agents / pharmacology
  • Benzimidazoles / pharmacology*
  • Biphenyl Compounds / pharmacology*
  • Carcinoma, Lewis Lung / drug therapy*
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / pathology
  • Cell Division / drug effects
  • Drug Screening Assays, Antitumor
  • Fibrosarcoma / drug therapy*
  • Fibrosarcoma / metabolism
  • Fibrosarcoma / pathology
  • Immunohistochemistry
  • Lisinopril / pharmacology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Neoplasm Metastasis / prevention & control
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / prevention & control
  • Peptidyl-Dipeptidase A / biosynthesis
  • Peptidyl-Dipeptidase A / genetics
  • RNA, Messenger / biosynthesis
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin / biosynthesis
  • Receptors, Angiotensin / genetics
  • Sarcoma 180 / drug therapy
  • Sarcoma 180 / metabolism
  • Sarcoma 180 / pathology
  • Sarcoma, Experimental / drug therapy*
  • Sarcoma, Experimental / metabolism
  • Sarcoma, Experimental / pathology
  • Signal Transduction / drug effects*
  • Tetrazoles*

Substances

  • Angiotensin Receptor Antagonists
  • Antihypertensive Agents
  • Antineoplastic Agents
  • Benzimidazoles
  • Biphenyl Compounds
  • RNA, Messenger
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin
  • Tetrazoles
  • Lisinopril
  • Peptidyl-Dipeptidase A
  • candesartan cilexetil