Cell cycle inhibition by the anti-angiogenic agent TNP-470 is mediated by p53 and p21(WAF1/CIP1)

Angiogenesis has been demonstrated to be essential for tumor growth and met astasis, and inhibition of angiogenesis is emerging as a promising strategy for treating cancer. Among the most potent inhibitors of angiogenesis is t he fumagillin family of natural products. An analog of fumagillin, known as TNP-470 or AGM-1470. has been undergoing clinical trials for treating a va riety of cancers. TNP-470 has been shown to block endothelial cell cycle pr ogression in the late G(1) phase. Although the direct molecular target for TNP-470 has been identified as the type 2 methionine aminopeptidase (MetAP2 ). how inhibition of this enzyme leads to cell cycle arrest has remained un clear. We report that treatment of endothelial and other drug-sensitive cel l types leads to the activation of the p53 pathway, causing an accumulation of the G(1) cyclin-dependent kinase inhibitor p21(WAF1/CIP1). The requirem ent of p53 and p21(WAF1/CIP1) for the cell cycle inhibition by TNP-470 is u nderscored by the observation that cells deficient in p53 and p21(WAF1/CIP1 ) are resistant to TNP-470. These results shed significant light on the mec hanism of cell cycle inhibition by TNP-470 and suggest an alternative metho d of activating p53 in endothelial cells to halt angiogenesis and tumor pro gression.