title: Aminopeptidase N inhibitor 4cc synergizes antitumor effects of 5-fluorouracil on human liver cancer cells through ROS-dependent CD13 inhibition.
abstract: Aminopeptidase N (APN, also known as CD13) is involved in cellular processes of various types of tumors and a potential anti-cancer therapeutic target. Here, we report the effect of an APN inhibitor 4cc in enhancing sensitivity of hepatocellular carcinoma (HCC) cell lines and xenograft model in response to 5-fluorouracil (5-FU) in vivo and in vitro. The treatment of the combination of 4cc with 5-FU, compared to the combination of bestain with 5-FU, markedly suppressed cell growth and induced apoptosis of HCC cells, accompanying the increase in the level of reactive oxygen species (ROS) and followed by a decrease in the mitochondrial membrane potential (ΔΨM). Furthermore, the combination of 4cc and 5-FU showed a significant inhibitory effect on the growth of HCC xenograft tumors. In addition, following the treatment of 4cc, APN activity and clonogenic formation and the number of CD13-positive cells in PLC/PRF/5 cells were significantly decreased, suggesting that 4cc may also inhibit liver cancer stem cells by CD13 inhibition. These results showed that the APN inhibitor 4cc synergizes antitumor effects of 5-FU on human liver cancer cells via ROS-mediated drug resistance inhibition and concurrent activation of the mitochondrial pathways of apoptosis.
authors.affiliation: Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China.
authors.forename: Zhi-Peng
authors.initials: ZP
authors.lastname: Sun
authors.affiliation: Department of Medical Chemistry, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Shi
authors.affiliation: Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China.
authors.forename: Xiu-Rong
authors.initials: XR
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
authors.forename: Wen-Fang
authors.initials: WF
authors.lastname: Xu
authors.affiliation: Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China. Electronic address: daigong@wfmc.edu.cn.
authors.forename: Gong
authors.initials: G
authors.lastname: Dai
authors.affiliation: Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China. Electronic address: wangxuejian@wfmc.edu.cn.
authors.forename: Xue-Jian
authors.initials: XJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
chemical_list: C000606538:4-methyl-2-(3-(naphthalen-1-yl-methyl)ureido)pentanoic acid hydroxyamide; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; D014508:Urea; D018826:CD13 Antigens; D007930:Leucine; D005472:Fluorouracil
keywords: 4cc; 5-FU; Apotosis; CD13; Drug combination; Liver cancer; ROS; ΔΨM