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

Abstract Aminopeptidase N (APN/CD13) is an essential peptidase involved in the process of tumor growth, metastasis and angiogenesis. 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 S1 and...

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Bibliographic Details
Published in:Cancer letters 2010-06, Vol.292 (2), p.153-162
Main Authors: Cui, Shu-Xiang, Qu, Xian-Jun, Gao, Zu-Hua, Zhang, Yu-Sheng, Zhang, Xiao-Fan, Zhao, Cui-Rong, Xu, Wen-Fang, Li, Qian-Bin, Han, Jin-Xiang
Format: Article
Language:English
Subjects:
Aminopeptidase N (APN/CD13)
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Binding sites
Blotting, Western
Cancer
CD13 Antigens - antagonists & inhibitors
Cell adhesion & migration
Cell culture
Cell Division - drug effects
Cell Line, Tumor
CIP-13F
Cyclic-imide peptidomimetics
Enzymes
Female
Flow Cytometry
Hematology, Oncology and Palliative Medicine
Humans
Imides - chemistry
Inhibitory effect
Mice
Mice, Inbred BALB C
Mice, Nude
Models, Molecular
Molecular Mimicry
Ovarian carcinoma (OVCA)
Ovarian Neoplasms - enzymology
Ovarian Neoplasms - pathology
Peptides, Cyclic - chemistry
Peptides, Cyclic - pharmacology
Piperidines - pharmacology
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Signal transduction
Studies
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Summary:Abstract Aminopeptidase N (APN/CD13) is an essential peptidase involved in the process of tumor growth, metastasis and angiogenesis. 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 S1 and S′1 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 HRA 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 caudalis 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.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2009.11.021