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Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model
Author(s) -
Chun Eunyoung,
Han Cheol Kyu,
Yoon Jeong Hyeok,
Sim Tae Bo,
Kim YoonKeun,
Lee KiYoung
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20687
Subject(s) - angiogenesis , in vivo , cancer research , apoptosis , cell growth , umbilical vein , growth inhibition , biology , cell cycle , nude mouse , pharmacology , angiogenesis inhibitor , in vitro , biochemistry , microbiology and biotechnology
Abstract Inhibition of angiogenesis is emerging as a promising strategy for the treatment of cancer. In our study reported here, the effects of 4 highly potent methionine aminopeptidase 2 (MetAP2) inhibitors, IDR‐803, IDR‐804, IDR‐805 and CKD‐732 (designed by structure‐based molecular modeling), on angiogenesis and tumor growth were assessed. Concentrations of these inhibitors as low as 2.5 nM were able to inhibit the growth of human umbilical vein endothelial cells (HUVEC) by as much as 50%, arresting growth in the G 1 stage of mitosis. An intracellular accumulation of p21 WAF1/Cip1 protein was also observed. Furthermore, at higher concentrations (25 nM) of these 4 MetAP2 inhibitors, a significant induction of apoptosis was apparent in the same HUVEC cultures. As a result of these findings, the possible anticancer effects of these inhibitors were examined, utilizing the SNU‐398 hepatoma cell line. Interestingly, pretreatment with these inhibitors led to an increased number of apoptotic cells of up to 60% or more, compared to untreated controls. Moreover, utilizing an in vivo xenografted murine model, these inhibitors suppressed the growth of engrafted tumor. In conclusion, these 4 inhibitory compounds potently exert an antiangiogenic effect to inhibit the growth of cancers in vivo and could potentially be useful for the treatment of a variety of cancers. © 2004 Wiley‐Liss, Inc.