title: Quinoline-based clioquinol and nitroxoline exhibit anticancer activity inducing FoxM1 inhibition in cholangiocarcinoma cells.
abstract: OBJECTIVE
  Fork head box M1 (FoxM1) is an oncogenic transcription factor frequently elevated in numerous cancers, including cholangiocarcinoma (CCA). A growing body of evidence documents its diverse functions contributing to tumorigenesis and cancer progression. As such, discovery of agents that can target FoxM1 would be valuable for the treatment of CCA. The quinoline-based compounds, namely clioquinol (CQ) and nitroxoline (NQ), represent a new class of anticancer drug. However, their efficacy and underlying mechanisms have not been elucidated in CCA. In this study, anticancer activities and inhibitory effects of CQ and NQ on FoxM1 signaling were explored using CCA cells.
  
  
  METHODS
  The effects of CQ and NQ on cell viability and proliferation were evaluated using the colorimetric 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-(4-sulfophenyl)-2H-tetrazolium (MTS assay). Colony formation and cell migration affected by CQ and NQ were investigated using a clonogenic and a wound healing assay, respectively. To demonstrate the agents' effects on FoxM1 signaling, expression levels of the target genes were quantitatively determined using real-time polymerase chain reaction.
  
  
  RESULTS
  CQ and NQ significantly inhibited cell survival of HuCCT1 and Huh28 in a dose- and a time-dependent fashion. Further investigations using the rapidly proliferating HuCCT1 cells revealed significant suppression of cell proliferation and colony formation induced by low doses of the compounds. Treatment of CQ and NQ repressed expression of cyclin D1 but enhanced expression of p21. Most importantly, upon CQ and NQ treatment, expression of oncogenic FoxM1 was markedly decreased concomitant with downregulation of various FoxM1's downstream targets including cdc25b, CENP-B, and survivin. In addition, the compounds distinctly impaired HuCCT1 migration as well as inhibited expression of matrix metalloproteinase (MMP)-2 and MMP-9.
  
  
  CONCLUSIONS
  Collectively, this study reports for the first time the anticancer effects of CQ and NQ against CCA cells, and highlights new insights into the mechanism of actions of the quinoline-based compounds to disrupt FoxM1 signaling.
authors.affiliation: Center for Research and Innovation, Mahidol University, Bangkok, Thailand.
authors.forename: Waraporn
authors.initials: W
authors.lastname: Chan-On
authors.affiliation: Department of Clinical Microbiology and Applied Technology, Mahidol University, Bangkok, Thailand.
authors.forename: Nguyen Thi Bich
authors.initials: NT
authors.lastname: Huyen
authors.affiliation: Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
authors.forename: Napat
authors.initials: N
authors.lastname: Songtawee
authors.affiliation: Center for Research and Innovation, Mahidol University, Bangkok, Thailand.
authors.forename: Wilasinee
authors.initials: W
authors.lastname: Suwanjang
authors.affiliation: Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
authors.forename: Supaluk
authors.initials: S
authors.lastname: Prachayasittikul
authors.affiliation: Department of Clinical Microbiology and Applied Technology, Mahidol University, Bangkok, Thailand.
authors.forename: Virapong
authors.initials: V
authors.lastname: Prachayasittikul
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D007464:Clioquinol / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009600:Nitroquinolines / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D009600:Nitroquinolines; D011804:Quinolines; D007464:Clioquinol; C005308:nitroxoline; C037219:quinoline
keywords: 8-hydroxyquinoline derivatives; FoxM1; cholangiocarcinoma; clioquinol; migration; nitroxoline