Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model

Eunyoung Chun, Cheol Kyu Han, Jeong Hyeok Yoon, Taebo Sim, Yoon Keun Kim, Ki Young Lee

Research output: Contribution to journalArticle

48 Citations (Scopus)

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 (MetAPZ) 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, stage of mitosis. An intracellular accumulation of p21WAF1/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.

Original languageEnglish
Pages (from-to)124-130
Number of pages7
JournalInternational Journal of Cancer
Volume114
Issue number1
DOIs
Publication statusPublished - 2005 Mar 10
Externally publishedYes

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Keywords

  • Angiogenesis
  • Apoptosis
  • Endothelial cells
  • Tumor immunity

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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