title: Quantitative high-throughput drug screening identifies novel classes of drugs with anticancer activity in thyroid cancer cells: opportunities for repurposing.
abstract: BACKGROUND
  Despite increased understanding of the pathogenesis and targets for thyroid cancer and other cancers, developing a new anticancer chemical agent remains an expensive and long process. An alternative approach is the exploitation of clinically used and/or bioactive compounds.
  
  
  OBJECTIVE
  Our objective was to identify agents with an anticancer effect in thyroid cancer cell lines using quantitative high-throughput screening (qHTS).
  
  
  METHODS
  We used the newly assembled National Institutes of Health Chemical Genomic Center's pharmaceutical collection, which contains 2816 clinically approved drugs and bioactive compounds to perform qHTS.
  
  
  RESULTS
  Multiple agents, across a variety of therapeutic categories and with different modes of action, were found to have an antiproliferative effect. We found the following therapeutic categories were the most enriched categories with antiproliferative activity: cardiotonic and antiobesity agents. Sixteen agents had an efficacy of greater than 60% and a 50% inhibitory concentration (IC50) in the nanomolar range. We validated the results of the qHTS using two agents (bortezomib and ouabain) in additional cell lines representing different histological subtypes of thyroid cancer and with different mutations (BRAF V600E, RET/PTC1, p53, PTEN). Both agents induced apoptosis, and ouabain also caused cell cycle arrest.
  
  
  CONCLUSIONS
  To our knowledge, this is the first study to use qHTS of a large drug library to identify candidate drugs for anticancer therapy. Our results indicate such a screening approach can lead to the discovery of novel agents in different therapeutic categories and drugs with nonclassic chemotherapy mode of action. Our approach could lead to drug repurposing and accelerate clinical trials of compounds with well-established pharmacokinetics and toxicity profiles.
authors.affiliation: Endocrine Oncology Section, Surgery Branch, National Cancer Institute, Clinical Research Center, Building 10-CRC, Room 3-3940, 10 Center Drive, MSC 1201, Bethesda, Maryland 20892, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhang
authors.forename: Mei
authors.initials: M
authors.lastname: He
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Naris
authors.initials: N
authors.lastname: Nilubol
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents