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 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.

• Authors: Shu-Xiang Cui, Xian-Jun Qu, Zu-Hua Gao, Yu-Sheng Zhang, Xiao-Fan Zhang, Cui-Rong Zhao, Wen-Fang Xu, Qian-Bin Li, Jin-Xiang Han
• Journal: Cancer letters (Cancer Lett) Vol. 292 Issue 2 Pg. 153-62 (Jun 28 2010) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 20042271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 2-amino-N-(1-(2-(hydroxyamino)-2-oxoethyl)-2,6-dioxopiperidin-3-yl)-3-phenylpropanamide
• Antineoplastic Agents
• Imides
• Peptides, Cyclic
• Piperidines
• Protease Inhibitors
• CD13 Antigens

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• CD13 Antigens (antagonists & inhibitors)
• Cell Division (drug effects)
• Cell Line, Tumor
• Female
• Flow Cytometry
• Humans
• Imides (chemistry)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Models, Molecular
• Molecular Mimicry
• Ovarian Neoplasms (enzymology, pathology)
• Peptides, Cyclic (chemistry, pharmacology)
• Piperidines (pharmacology)
• Protease Inhibitors (chemistry, pharmacology)