title: A novel antitumor piperazine alkyl compound causes apoptosis by inducing RhoB expression via ROS‑mediated c‑Abl/p38 MAPK signaling.
abstract: OBJECTIVE
  We investigated the action mechanism of a novel anticancer compound, KR28 (1-allyl-4-dodecanoyl-1-ethyl-piperazin-1-ium; bromide), to induce apoptosis of human prostate carcinoma PC-3 cells.
  
  
  METHODS
  To explore an apoptotic signaling of KR28, we used ROS assay, SRB assay, flow cytometry analysis, reporter assay, xenograft assay, Western blotting, and RT-PCR analysis.
  
  
  RESULTS
  The growth inhibitory action of KR28 is cell line specific, impeding the growth of prostate carcinoma PC-3 and stomach carcinoma NUGC-3 cells. KR28 showed strong antitumor activity in PC-3 mouse xenograft model. KR28 increased ROS production, leading to nuclear c-Abl expression, which in turn activated p38 mitogen-activated protein kinase (MAPK) to enhance the expression of RhoB, an apoptosis inducer. The KR28-induced apoptosis was abrogated by the ROS scavenger N-acetylcysteine and by knockdown of c-Abl, p38 MAPK, or ATF2. Moreover, the p300 binding site and two CCAAT boxes in the RhoB promoter appear to be involved in ROS-mediated RhoB expression in the presence of KR28.
  
  
  CONCLUSIONS
  The antitumor agent KR28 induces apoptosis of PC-3 cells by ROS-mediated RhoB expression via c-Abl upregulation and activation of p38 MAPK/ATF-2.
authors.forename: Kyung-Sook
authors.initials: KS
authors.lastname: Chung
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
authors.forename: Bo-Kyung
authors.initials: BK
authors.lastname: Kim
authors.forename: Hwan-Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Jee Sun
authors.initials: JS
authors.lastname: Yang
authors.forename: Jiwon
authors.initials: J
authors.lastname: Ahn
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.forename: Kyung-Bin
authors.initials: KB
authors.lastname: Song
authors.forename: Misun
authors.initials: M
authors.lastname: Won
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000235:genetics
chemical_list: C586022:1-allyl-4-dodecanoyl-1-ethylpiperazin-1-ium; D000498:Allyl Compounds; D000970:Antineoplastic Agents; D010879:Piperazines; D017382:Reactive Oxygen Species; D016315:Proto-Oncogene Proteins c-abl; D048051:p38 Mitogen-Activated Protein Kinases; D020743:rhoB GTP-Binding Protein