title: Antitumor activity of antimicrobial peptides containing CisoDGRC in CD13 negative breast cancer cells.
abstract: BACKGROUND
  isoAsp-Gly-Arg (isoDGR) is a derivative of the Asn-Gly-Arg (NGR) motif, which is used as a targeted delivery tool to aminopeptidase N (CD13) positive cells. Recent studies have shown that cyclic isoDGR (CisoDGRC) has a more efficient affinity with α(v)β(3), a type of integrin that overexpresses in tumor cells. Antimicrobial peptides (AMPs) are an efficient antitumor peptide that specifically kills tumor cells. In the present study, we designed antimicrobial peptides containing the CisoDGRC motif (CDAK) and assessed its antitumor activity for CD13(-)/α(v)β(3) (+) breast cancer cells (MCF-7 and MDA-MB-231) in vitro and in vivo.
  
  
  METHODS
  
  We assessed the cytotoxicity of CDAK for MCF-7 and MDA-MB-231 breast cancer cells, the human umbilical vein endothelial cell (HUVEC), and human foreskin fibroblasts (HFF). We performed an apoptosis assay using Annexin-V/PI, DNA ladder, mitochondrial membrane potential, and Caspase-3 and Bcl-2. The effect on cell cycles and affinity with cell were tested using flow cytometry and fluorescent microscopy and the effect on invasion was analyzed using an invasion assay. CDAK was injected intravenously into tumor-bearing athymic nude mice in vivo experiment.
  
  
  RESULTS
  CDAK showed cytotoxic activity in MCF-7 and MDA-MB-231 cells, whereas HUVEC and HFF were less sensitive to the peptides. CDAK induced apoptosis, reduced mitochondrial membrane potential, promoted Caspase-3, and inhibited Bcl-2 expression in the two breast cancer cell lines. In addition, CDAK inhibited proliferation of cancer cell through S phase arrest, and own selective affinity with MCF-7 and MDA-MB-231cells, inhibited the invasion of MDA-MB-231 cells. In vivo, CDAK significant inhibited the progression of the tumor and the generation of neovascularization.
  
  
  CONCLUSIONS
  Antimicrobial peptides containing the CisoDGRC (CDAK) motif could efficiently exhibit the antitumor activity for CD13(-)/α(v)β(3) (+) breast cancer cells.
authors: Department of Oncology, The First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
authors: Lei
authors: L
authors: Hou
authors: Xinhan
authors: X
authors: Zhao
authors: Pei
authors: P
authors: Wang
authors: Qian
authors: Q
authors: Ning
authors: Min
authors: M
authors: Meng
authors: Caigang
authors: C
authors: Liu
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018826:CD13 Antigens / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; D018826:CD13 Antigens