‘Angioprevention’: angiogenesis is a common and key target for cancer chemopreventive agents

Abstract

The potential to block tumor growth by inhibition of the neoangiogenic process represents an intriguing approach to the treatment of solid tumors. The high proliferation rate in the tumor deprived of proper vascularization would be balanced by cell death due to lack of diffusion of nutrients and oxygen. Matrix metalloproteinases (MMPs), angiogenic growth factors, and their receptors are the main targets of an increasing number of clinical trials approved to test the tolerance and therapeutic efficacy of antiangiogenic agents. We observed that a series of substances proposed as possible cancer chemopreventive agents show antiangiogenic properties when tested in in vitro and in vivo angiogenesis models. We demonstrated that N‐acetyl ‐L ‐cysteine is able to reduce the invasive and metastatic potential of melanoma cells, and to inhibit endothelial cell invasion by direct inhibition of MMP activity. We also showed that epigallocatechin gallate (EGCG), a flavonoid from green tea that possesses chemopreventive activity in experimental and epidemi‐ological studies, is a potent inhibitor of MMP‐2 and MMP‐9. Angiogenesis has also been demonstrated to be a target for nonsteroidal anti‐inflammatory drug che‐mopreventive activity. Based on these data, we hypothesize that other chemopreventive agents, including natural or synthetic retinoids, steroid hormone antagonists, peroxisome proliferator‐activated receptor γ li‐gands, vitamin D, and protease inhibitors, might have antiangiogenesis as an important mechanism of action, a novel concept we will term ‘angioprevention’. We analyze the mechanisms on how and why chemopreven‐tive agents could exert antiangiogenic effects aimed at controlling tumor growth, and their potential use in the clinic.—Tosetti, F., Ferrari, N., De Flora, S., Albini, A. ‘Angioprevention’: angiogenesis is a common and key target for cancer chemopreventive agents. FASEB J. 16, 2–14 (2002)