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

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Abstract
Angiogenesis has been demonstrated to be essential for tumor growth and metastasis, and inhibition of angiogenesis is emerging as a promising strategy for treating cancer. Among the most potent inhibitors of angiogenesis is the fumagillin family of natural products. An analog of fumagillin, known as TNP-470 or AGM-1470, has been undergoing clinical trials for treating a variety of cancers. TNP-470 has been shown to block endothelial cell cycle progression in the late G1 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 unclear. We report that treatment of endothelial and other drug-sensitive cell types leads to the activation of the p53 pathway, causing an accumulation of the G1 cyclin-dependent kinase inhibitor p21WAF1/CIP1. The requirement of p53 and p21WAF1/CIP1 for the cell cycle inhibition by TNP-470 is underscored by the observation that cells deficient in p53 and p21WAF1/CIP1 are resistant to TNP-470. These results shed significant light on the mechanism of cell cycle inhibition by TNP-470 and suggest an alternative method of activating p53 in endothelial cells to halt angiogenesis and tumor progression.