LYP, a novel bestatin derivative, inhibits cell growth and suppresses APN/CD13 activity in human ovarian carcinoma cells more potently than bestatin

• Published in: Investigational new drugs 2011-08, Vol.29 (4), p.574-582
• Main Authors: Gao, Jian-Jun, Gao, Zu-Hua, Zhao, Cui-Rong, Yuan, Yi, Cui, Shu-Xiang, Zhang, Xiao-Fan, Cheng, Yan-Na, Xu, Wen-Fang, Tang, Wei, Qu, Xian-Jun
• Format: Article
• Language: English
• Subjects: Animals; Cancer; CD13 Antigens - antagonists & inhibitors; CD13 Antigens - metabolism; Cell culture; Cell growth; Cell Line, Tumor; Cell Membrane - drug effects; Cell Membrane - enzymology; Cell Proliferation - drug effects; Esters; Female; Flow cytometry; Humans; Inhibitor drugs; Laboratories; Leucine - analogs & derivatives; Leucine - chemistry; Leucine - pharmacology; Medicine; Medicine & Public Health; Mice; Oncology; Ovarian cancer; Ovarian Neoplasms - blood; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - pathology; Ovaries; Pharmaceuticals; Pharmacology; Pharmacology/Toxicology; Preclinical Studies; Signal transduction; Studies; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-010-9391-9

Summary LYP is a bestatin dimethylaminoethyl ester which inhibits aminopeptidase N (APN/CD13). Our goal in this study was to evaluate LYP as a candidate compound for cancer treatment, beginning by studying its inhibitory effects on tumors and then comparing it to bestatin. Experiments were performed on human ovarian carcinoma (OVCA) ES-2 and SKOV-3 cell lines, which have high and low levels of APN/CD13 respectively. LYP effectively inhibited ES-2 cell growth as estimated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and the trypan blue dye-exclusion test. LYP significantly suppressed APN/CD13 activity on the surface of ES-2 cells as measured by quantifying the enzymatic cleavage of the substrate L-leucine- p -nitroanilide. The inhibitory effects of LYP were greater than those of bestatin at the same concentrations. In contrast, LYP was a weak inhibitor of SKOV-3 cell growth, suggesting that LYP may inhibit ES-2 cell growth via suppression of APN/CD13. Inhibition of APN/CD13 expression was also demonstrated with immunofluorescent flow cytometry and Western blot analysis. Inhibitory effects of LYP were confirmed by using a mouse model in which LYP delayed the growth of ES-2 xenografts in mice after 2 weeks of LYP injections. Inhibition of APN/CD13 expression was demonstrated in the ES-2 xenografts using Western blot analysis. The inhibitory effects of LYP on the ES-2 xenografts were stronger than those of bestatin. These results suggest that LYP has a powerful inhibitory effect on the growth of OVCA cells and that the mechanism may be via a decrease in the expression of APN/CD13.