title: Preliminary detection of the anti‑tumour activity of indoline‑2,3‑dione derivative DH‑12a targeting aminopeptidase N.
abstract: Aminopeptidase N (APN) is important in tumour processes. The present study detected the anti‑tumour activity of the novel APN inhibitor DH‑12a, which is an indoline‑2,3‑dione derivative. In the present study, Bestatin, a clinical APN inhibitor was used as a positive control. The expression of APN in the ES-2 and 3AO cell lines were assessed using flow cytometry and the drug inhibition constants of DH‑12a (Ki=13.15 µM) and Bestatin (Ki=16.57 µM) were assessed using a double reciprocal method of competitive inhibition. The in vitro effects of DH‑12a on cell proliferation were assessed using a 3‑(4,5‑dimethyl‑thiazol‑2‑yl)‑2,5‑diphenyl tetrazolium bromide assay on human cell lines of ES‑2 (IC50=43.8 µM), A549 (inhibition rate=41.5% at 160 µM DH‑12a), HL60 (inhibition rate=47.83% at 160 µM DH‑12a) and 3AO (IC50=70.2 µM). The inhibition rates were consistently higher than those of Bestatin. The effects of DH‑12a on cell migration (inhibition rates in ES‑2 cells and 3AO cells were 56.4 and 76.5%, respectively at 15 µM) and invasion (inhibition rates in ES‑2 cells and 3AO cells were 75.6 and 66.5%, respectively at 15 µM) were assessed using transwell plates. The in vivo effects of DH‑12a on tumour proliferation and lung tumour metastasis were determined using an H22 xenograft mice model, where DH‑12a was administered in combination with genotoxic 5‑fluorouracil. The anti‑tumour activities of DH‑12a in vivo were also greater than those of Bestatin. In conclusion, the in vitro effects of DH‑12a on tumour proliferation, migration and invasion were consistent with the in vivo effects. In addition, DH‑12a exhibited greater anti‑tumour properties compared with Bestatin.
authors.affiliation: Pharmacy and Biological Science College, Weifang Medical University, Weifang, Shandong 261053, P.R. China.
authors.forename: De-Xuan
authors.initials: DX
authors.lastname: Cui
authors.affiliation: Pharmacy and Biological Science College, Weifang Medical University, Weifang, Shandong 261053, P.R. China.
authors.forename: Xue-Jian
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Pharmacy and Biological Science College, Weifang Medical University, Weifang, Shandong 261053, P.R. China.
authors.forename: Xiu-Rong
authors.initials: XR
authors.lastname: Zhang
authors.affiliation: Pharmacy and Biological Science College, Weifang Medical University, Weifang, Shandong 261053, P.R. China.
authors.forename: Ting-Kun
authors.initials: TK
authors.lastname: Zhao
authors.affiliation: Sino‑India Computer Software Institute, Weifang University of Science and Technology, Shouguang, Shandong 262700, P.R. China.
authors.forename: Xiu-Xiang
authors.initials: XX
authors.lastname: Guo
authors.affiliation: Pharmacy and Biological Science College, Weifang Medical University, Weifang, Shandong 261053, P.R. China.
authors.forename: Shun-Mei
authors.initials: SM
authors.lastname: Liu
authors.affiliation: Weifang High‑tech Zone Biomedical Science and Technology Industrial Park, Weifang, Shandong 261205, P.R. China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Weifang High‑tech Zone Biomedical Science and Technology Industrial Park, Weifang, Shandong 261205, P.R. China.
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Ma
authors.affiliation: Pharmacy and Biological Science College, Weifang Medical University, Weifang, Shandong 261053, P.R. China.
authors.forename: Zhi-Qin
authors.initials: ZQ
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000598416:2-(5'-chloro-2'-oxospiro((1,3)dioxepane-2,3'-indoline)-1'-yl)-N-hydroxyacetamide; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D007211:Indoles; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex; D005472:Fluorouracil