Class-specific pro-apoptotic effect of statins on human vascular endothelial cells

Abstract

Neonangiogenesis represents an important step in tumor development and propagation. Statins may have anticancerogenic potential by blocking vascular endothelial cell growth. The antiproliferative effect of four statins on human endothelial cells was compared, concomitantly delineating a possible pro-apoptotic process. All four statins tested, i. e. atorvastatin, fluvastatin, lovastatin, and simvastatin inhibited cell proliferation. Nearly complete blocking of cell proliferation was achieved at a concentration of 10 microM. We were able to demonstrate that the antiproliferative effect of the statins is not due to cytotoxicity but rather to an apoptotic effect as demonstrated by comparison of cytotoxicity assay and apoptosis assay. The apoptotic mechanism seems to involve caspases, since the statins significantly enhanced caspase activity at dosages of 10 and 20 microM. Further experiments revealed a downregulation of the pro-apoptotic protein Bcl-2. Our data indicate that statins may class-specific inhibit angiogenesis at high dosages which can contribute to prevention of tumor development and progression.

Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, potentiate the anti-angiogenic effects of bevacizumab by suppressing angiopoietin2, BiP, and Hsp90α in human colorectal cancer

“…Several studies have suggested that the anti-angiogenic activity of statins is achieved by inhibiting proliferation and migration of endothelial cells, as well as inducing cell apoptosis (Negre-Aminou et al , 1997; Pirillo et al , 1997; Sato et al , 1998; Kaneta et al , 2003; Muck et al , 2004; Schaefer et al , 2004); however, these studies used high concentrations of statins ranging from 2 to 100  μ M in vitro . To reach serum concentrations of 2–20  μ M , simvastatin has to be administered at a daily dose of 100–200 mg kg −1 , a dose not feasible for human use.…”

“…On the other hand, at high micromolar concentrations, they have anti-angiogenic activity and may be of special significance for cancer therapy. The anticancer effects of statins have been shown to result from the inhibition of endothelial cell proliferation and migration, as well as the induction of apoptosis (Negre-Aminou et al , 1997; Pirillo et al , 1997; Sato et al , 1998; Kaneta et al , 2003; Muck et al , 2004; Schaefer et al , 2004); however, a limitation in using statins for cancer therapy is that the required doses are too high to be applied to patients.…”

“…In this present study, we investigated whether cardiovascular therapeutic doses of statins affect angiogenesis and potentiate anti-angiogenic effects of bevacizumab in CRC. On the basis of several previous results (Sato et al , 1998; Kaneta et al , 2003; Muck et al , 2004; Schaefer et al , 2004; Lee et al , 2006), we postulated that the statin dose used had little direct effect on endothelial cells; therefore, we focused on the mediators of angiogenesis. The mechanism underlying the anti-angiogenic effects of statins was evaluated by angiogenesis antibody array and proteomics analysis.…”

Improved survival with continuation of statins in bacteremic patients

“… 28 , 29 Statins may also have a direct antimicrobial effect, 30 and possible antibacterial activity of statins against a variety of pathogens may be attributed to their ability to suppress cell growth, and to promote apoptosis. 31 – 33 …”

Simvastatin Induces Apoptosis of Fibroblast-Like Synoviocytes~!2009-02-16~!2009-03-24~!2009-09-07~!

“…It has been suggested that reduced apoptosis contributes to the synovial inflammatory process [12]. In vitro statins were shown to exert a cytotoxic effect on human T, B and myeloma cells by promoting their apoptosis [14] and also modifying apoptosis of smooth muscle and endothelial cells leading to altered vascular function and neovascularisation [15]. …”