The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor.
Angiotensin-I converting enzyme (ACE) inhibitor is used widely as an antihypertensive agent, and it has been suggested recently that it decreases the risk of cancer (A. F. Lever et al., Lancet, 352: 179-184, 1998). In this study, we examined the effect of several ACE inhibitors and angiotensin-II type 1 receptor (AT(1)-R) antagonists on tumor development and angiogenesis in a murine hepatocellular carcinoma model. Among ACE inhibitors, perindopril appeared to be a potent inhibitor of tumor development and angiogenesis, whereas AT(1)-R antagonists did not exert such an inhibitory effect. The inhibitory effect of perindopril was achieved even on established tumors. The level of the potent angiogenic factor, vascular endothelial growth factor (VEGF), in the tumor was significantly suppressed by perindopril. In vitro studies showed that perindopril-derived active form, perindoprilat, suppressed the endothelial cell tubule formation. Perindoprilat treatment also significantly inhibited VEGF mRNA expression in BNL-HCC cells in vitro. These results showed that the ACE inhibitor perindopril inhibited tumor development and angiogenesis independent from AT(1)-R blockage, and that VEGF alternation may be involved in the mechanism of this inhibitory effect. Because perindopril is widely used in clinical practice, it may represent an effective new strategy for anticancer therapy.
Yoshiji
H
H
Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara Nara 634-8522, Japan. yoshijih@naramed-u.ac.jp
Kuriyama
S
S
Kawata
M
M
Yoshii
J
J
Ikenaka
Y
Y
Noguchi
R
R
Nakatani
T
T
Tsujinoue
H
H
Fukui
H
H
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D008222:Lymphokines / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D020913:Perindopril / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020913:Perindopril