Targeting aminopeptidase N (APN/CD13) with cyclic-imide peptidomimetics derivative CIP-13F inhibits the growth of human ovarian carcinoma cells

被引：41

作者：

Cui, Shu-Xiang ^{[1
,2
]}

Qu, Xian-Jun ^{[3
]}

Gao, Zu-Hua ^{[4
,5
]}

Zhang, Yu-Sheng ^{[3
]}

Zhang, Xiao-Fan ^{[3
]}

Zhao, Cui-Rong ^{[3
]}

Xu, Wen-Fang ^{[3
]}

Li, Qian-Bin ^{[3
]}

Han, Jin-Xiang ^{[1
]}

机构：

[1] Shandong Med Biotechnol Ctr, Jinan 250062, Peoples R China

[2] Shandong Acad Med Sci, Inst Mat Med, Dept Pharmacol, Jinan 250062, Peoples R China

[3] Shandong Univ, Sch Pharmaceut Sci, Dept Pharmacol, Jinan 250012, Peoples R China

[4] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB, Canada

[5] Calgary Lab Serv, Calgary, AB, Canada

来源：

CANCER LETTERS | 2010年 / 292卷 / 02期

关键词：

Aminopeptidase N (APN/CD13); Ovarian carcinoma (OVCA); Cyclic-imide peptidomimetics; CIP-13F; Inhibitory effect; Apoptosis; ENDOTHELIAL-CELLS; ESCHERICHIA-COLI; IN-VITRO; LINES; APOPTOSIS; N/CD13; CYTOTOXICITY; EXPRESSION; BESTATIN; PATHWAYS;

D O I：

10.1016/j.canlet.2009.11.021

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Aminopeptidase N (APN/CD13) is an essential peptidase involved in the process of tumor growth, metastasis and angtogenesis. Inhibition of APN/CD13 may be an effective strategy for cancer treatment. CIP-13F is a cyclic-imide peptidomimetics compound designed to fit the active pockets Si and SI of APN/CD13 that act in tumor proliferation Our aim in this study was to evaluate the efficacy of CIP-13F as a candidate compound for cancer treatment The experiments were performed on the human ovarian carcinoma (OVCA) ES-2 and FIRA cell lines, which have high and low levels of APN/CD13 respectively. CIP-13F significantly blocked APN/CD13 activity on the surface of ES-2 cells as measured by quantitating the enzymatic cleavage of the substrate L-leucine-p-nitroanilide CIP-13F effectively inhibited ES-2 cell growth and migration without significant cytotoxic effect In contrast, CIP-13F did not significantly inhibit HRA cell growth, indicating that CIP-13F may inhibit ES-2 cell growth via suppression of APN/CD13 The suppression of APN/CD13 was also observed by using the assays of flow cytometry and Western blot analysis Further, the inhibitory effects of CIP-13F on APN/CD13 and on ES-2 proliferation were supported by the induction of ES-2 apoptosis CIP-13F-treated ES-2 cells resulted apoptotic characteristics, such as induction of externalization of phosphatidylserine and DNA laddering fragment The activation of caspase-3 and poly ADP-ribose polymerase (PARP) was also enhanced. The inhibitory effects of CIP-13F on APN/CD13 expression and on ES-2 proliferation were confirmed in mice bearing ES-2 xenografts. CIP-13F delayed the growth of ES-2 xenografts in mice after 2 weeks of vena caudal's injection These results suggest that CIP-13F has a high inhibitory effect on the growth of OVCA cells via decreasing the activity and expression of APN/CD13 (C) 2009 Elsevier Ireland Ltd All rights reserved

引用

页码：153 / 162

页数：10

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