Several lines of evidence have suggested that acquisition of the angiogenic phenotype could be both a very early and an essential step during cancer development, making angiogenesis a potentially promising target for chemoprevention (Bergers, Javaherian, Lo, Folkman and Hanahan 1999; Black 1997). Advantages of angiopreventive strategies include lack of drug resistance and possibly low-toxicity of antiangiogenesis inhibitors, both of which are important for chemoprevention that usually requires long-term administration. Key to the development of successful angiopreventive strategies, however, is to identify non-toxic angiogenesis inhibitors that effectively suppress angiogenesis and early cancer development. We and others have recently shown that HMG-CoA reductase (HMG-CoA-R) inhibitors, designated statins, inhibit angiogenesis in vitro as well as in vivo, suggesting a potential use of statins as a new class of angiogenesis inhibitors. In the clinic, statins were originally designed to reduce cholesterol biosynthesis, a process catalyzed by HMG-CoA-R, and have been extensively used as prevention drugs against hyperlipidemia and cardiovascular conditions. Notably, inhibition of HMG-CoA-R also leads to suppression of geranylgeranylation (GGP) and farnesylation of proteins that mediate cell survival and proliferation signals, such as the Ras- and Rho-family. Our studies showed that HMG-CoA-R inhibition by statins selectively induce apoptosis in angiogenic endothelial cells (EC), whereas the growth of fibroblasts, epithelial cells, various tumor cell lines and quiescent EC was minimally affected. Mechanistic studies found that the anti-EC effect of statins was mediated by β4-integrin upregulation and survivin downregulation. Thus, our research suggested that the HMG-CoA-R/GGP/integrin/survivin axis might constitute a novel survival pathway in EC and could be a potential target for antiangiogenic approaches. Interestingly, we also demonstrated that in addition to its pro-apoptotic effect, statin also triggered survival signals in EC via the PI-3K/Akt pathway in a manner independent of HMG-CoA-R inhibition, thereby compromising its own anti-EC activity. Suppression of PI-3K activation released EC from the survival/death dilemma, and combination of statin and PI-3K inhibitors robustly enhanced the antiangiogenic effects of ATV in vitro as well as in vivo. Our data suggested the HMG-CoA-R pathway might play an important role in the angiogenic switch during early cancer development. Using a head and neck cancer model, animal studies demonstrated that statin potently delayed and suppressed tumor growth in prevention and therapeutic settings. These data have provided a rationale basis for developing angiopreventive strategies using statins at non-toxic oral doses. Because statins have been extensively used as safe clinical drugs, statin-based regimen might represent an attractive approach to cancer prevention.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]