Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats.

Abstract

Captopril, an inhibitor of angiotensin converting enzyme, is widely used clinically to manage hypertension and congestive heart failure. Here captopril is shown to be an inhibitor of angiogenesis able to block neovascularization induced in the rat cornea. Captopril acted directly and specifically on capillary endothelial cells, inhibiting their chemotaxis with a biphasic dose-response curve showing an initial decrease at clinically achievable doses under 10 M and a further slow decline in the millimolar range. Captopril inhibition of endothelial cell migration was not mediated by angiotensin converting enzyme inhibition, but was suppressed by zinc. Direct inhibition by captopril of zinc-dependent endothelial cell-derived 72-and 92-kD metalloproteinases known to be essential for angiogenesis was also seen. When used systemically on rats captopril inhibited corneal neovascularization and showed the antitumor activity expected of an inhibitor of angiogenesis, decreasing the number of mitoses present in carcinogen-induced foci of preneoplastic liver cells and slowing the growth rate of an experimental fibrosarcoma whose cells were resistant to captopril in vitro. These data define this widely used drug as a new inhibitor of neovascularization and raise the possibility that patients on long term captopril therapy may derive unexpected benefits from its antiangiogenic activities. ( J. Clin. Invest. 1996. 98: 671-679.)

Captopril inhibits tumour growth in a xenograft model of human renal cell carcinoma

“…In culture it inhibits vascular endothelial cell migration and collagenase production, which are both critical to angiogenesis in vivo. These endothelial cell effects appear independent of ACE inhibition and are not seen with other ACE inhibitors (Volpert et al, 1996).…”

“…Chemically-induced hepatic tumours in rats (Volpert et al, 1996) and pancreatic duct carcinoma in hamsters (Reddy et al, 1995) have also recently been shown to be dramatically reduced with captopril. This appears to be due to inhibition of mitosis as the proliferation of preneoplastic cells was reduced by captopril before actual tumour formation.…”

“…Captopril has been shown previously to be an effective inhibitor of angiogenesis. In the rat, it inhibits aortic and microvascular growth and prevents induction of corneal neovascularization (Volpert et al, 1996). In culture it inhibits vascular endothelial cell migration and collagenase production, which are both critical to angiogenesis in vivo.…”

Angiotensin inhibition and malignancies: a review

“…The capacity of ARBs for molecular targeting affecting both mitogenesis and angiogenesis in prostate cancer was also shown by Uemura et al 19,20 Liver cancer Experimental studies have shown that the ACE inhibitors captopril and perindopril decrease preneoplastic lesions and hepatic carcinoma cell growth. 21,22 In mice with BNL-hepatic carcinoma, treatment with perindopril decreased tumour growth, angiogenesis and VEGF, unlike treatment with the ARBs losartan or candesartan, suggesting that the antineoplastic effect might be independent of the formation or action of Ang II. [23][24][25] However, Ang II induces the expression of the potent angiogenic factor VEGF, which would be expected to enhance tumour growth and migration.…”

“…48 Eye When used systemically on rats, captopril inhibited corneal neovascularization and showed the antitumour activity expected of an inhibitor of angiogenesis. 21 Sarcoma and fibrosarcoma Treatment with captopril inhibited fibrosarcoma growth in a rat model by slowing of growth rate of experimental fibrosarcoma, even though these cells were resistant to captopril in vitro. 21 Both the ARB TCV-116 and the ACEi lisinopril inhibited tumour growth, tumour-associated angiogenesis and metastasis in a murine model of sarcoma.…”