title: Repositioning of the anthelmintic drug mebendazole for the treatment for colon cancer.
abstract: OBJECTIVE
  In the present study, we screened a compound library containing 1,600 clinically used compounds with the aim to identify compounds, which potentially could be repositioned for colon cancer therapy.
  
  
  METHODS
  Two established colon cancer cell lines were tested using the fluorometric microculture cytotoxicity assay (FMCA). For compound comparison connectivity map (CMAP) analysis, NCI 60 data mining and protein kinase binding measurements were performed.
  
  
  RESULTS
  Sixty-eight compounds were defined as hits with activity in both of these cell lines (<40 % cell survival compared with control) at 10 μM drug concentration. Analysis of chemical similarity of the hit compounds revealed several distinct clusters, among them the antiparasitic benzimidazole group. Two of these compounds, mebendazole (MBZ) and albendazole (ABZ) are registered for human use. Data from the NCI 60 cell line panel revealed only modest correlation between MBZ and ABZ, indicating differences in mechanism of action. This was further supported when gene expression signatures were compared in the CMAP database; ABZ ranked very low when MBZ was used as the query signature. Furthermore, MBZ, but not ABZ, was found to significantly interact with several protein kinases including BCR-ABL and BRAF. Analysis of the diagnosis-specific activity of MBZ showed activity in 80 % of the colon cancer cell lines in the NCI 60 panel. Three additional colon cancer cell lines and three cell models with non-malignant phenotypes were subsequently tested, confirming selective colon cancer activity of MBZ.
  
  
  CONCLUSIONS
  MBZ seemingly has repositioning potential for colorectal cancer therapy.
authors.affiliation: Section of Oncology, Department of Radiology, Oncology and Radiation Science, Uppsala University, 751 85, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
authors.forename: Bengt
authors.initials: B
authors.lastname: Agerup
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
mesh_terms: D000871:Anthelmintics / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D058492:Drug Repositioning; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008463:Mebendazole / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D000871:Anthelmintics; D000970:Antineoplastic Agents; D008463:Mebendazole