title: 13F-1, a novel 5-fluorouracil prodrug containing an Asn-Gly-Arg (NO2) COOCH3 tripeptide, inhibits human colonic carcinoma growth by targeting Aminopeptidase N (APN/CD13).
abstract: 13F-1 is a 5-fluorouracil prodrug containing an Asn-Gly-Arg (NO2) COOCH3 tripeptide. 13F-1 might possess the activity against cancer growth by targeting Aminopeptidase N (APN/CD13). Our goal in this study was to evaluate the inhibitory effect of 13F-1 on the growth of human colonic carcinoma by both in vitro and in vivo studies. Experiments were performed in colonic carcinoma Colo205 cells, which highly express APN/CD13 on cell surface. The inhibition of 13F-1 on cancer cell growth was estimated by the colorimetric and clonogenic assays. The assays of Annexin V-FITC/PI and JC-1 fluorescence probe were employed to determine the apoptotic cells. Further experiment was performed in mice bearing Colo205 xenografts. 13F-1 was injected for three consecutive weeks. The specimens of Colo205 xenografts were removed for TUNEL staining and western blotting analysis. The expressions of APN/CD13 were analyzed by immunofluorescent flow cytometry and western blotting assays. 13F-1 significantly inhibited Colo205 cell proliferation. 13F-1 by injection delayed the expansion of Colo205 xenografts without significant toxicity to mice. The inhibitory effect of 13F-1 might arise from its role in apoptotic induction. Further analysis indicated that 13F-1 strongly inhibited APN/CD13 expression on cancer cell surface. In contrast, 5-FU did not affect APN/CD13 expression. These results indicated the mechanism of 13F-1 action that 13F-1׳s effect was associated with its role in suppression of APN/CD13 expression. Conclusion, 13F-1 could be developed as a promising agent for treatment of cancers with high expression of APN/CD13.
authors.affiliation: Evaluation Center for Food and Drug, Capital Medical University, Beijing, China.
authors.forename: Shu-Xiang
authors.initials: SX
authors.lastname: Cui
authors.affiliation: Department of Pharmacy, Affiliated Hospital, Tan Shan Medical University, Tanan, China.
authors.forename: Hou-Li
authors.initials: HL
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Wen-Fang
authors.initials: WF
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Chemical Biology & Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China. Electronic address: qxj@sdu.edu.cn.
authors.forename: Xian-Jun
authors.initials: XJ
authors.lastname: Qu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018826:CD13 Antigens / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000594742:13F-1 compound; C526428:NGR peptide; D009842:Oligopeptides; D011355:Prodrugs; D018826:CD13 Antigens; D005472:Fluorouracil
keywords: 5-Fluorouracil; Aminopeptidase N (APN/CD13); Apoptosis; Asparagine–glycine–arginine (NGR); Colon cancer