Dataset Information

Quantitative high-throughput drug screening identifies novel classes of drugs with anticancer activity in thyroid cancer cells: opportunities for repurposing.

ABSTRACT: 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.Our objective was to identify agents with an anticancer effect in thyroid cancer cell lines using quantitative high-throughput screening (qHTS).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.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.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.

SUBMITTER: Zhang L

PROVIDER: S-EPMC3319218 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Quantitative high-throughput drug screening identifies novel classes of drugs with anticancer activity in thyroid cancer cells: opportunities for repurposing.

Zhang Lisa L He Mei M Zhang Yaqin Y Nilubol Naris N Shen Min M Kebebew Electron E

The Journal of clinical endocrinology and metabolism 20111214 3

<h4>Context</h4>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.<h4>Objective</h4>Our objective was to identify agents with an anticancer effect in thyroid cancer cell lines using quantitative high-throughput screening (qHTS).<h4>Design</h4>We used the newly assembled Natio ...[more]

PMID: 22170715

Similar Datasets

Project description:Pseudomonas aeruginosa is the most common pathogen infecting cystic fibrosis (CF) lungs, causing acute and chronic infections. Intrinsic and acquired antibiotic resistance allow P. aeruginosa to colonize and persist despite antibiotic treatment, making new therapeutic approaches necessary. Combining high-throughput screening and drug repurposing is an effective way to develop new therapeutic uses for drugs. This study screened a drug library of 3,386 drugs, mostly FDA approved, to identify antimicrobials against P. aeruginosa under physicochemical conditions relevant to CF-infected lungs. Based on the antibacterial activity, assessed spectrophotometrically against the prototype RP73 strain and 10 other CF virulent strains, and the toxic potential evaluated toward CF IB3-1 bronchial epithelial cells, five potential hits were selected for further analysis: the anti-inflammatory and antioxidant ebselen, the anticancer drugs tirapazamine, carmofur, and 5-fluorouracil, and the antifungal tavaborole. A time-kill assay showed that ebselen has the potential to cause rapid and dose-dependent bactericidal activity. The antibiofilm activity was evaluated by viable cell count and crystal violet assays, revealing carmofur and 5-fluorouracil as the most active drugs in preventing biofilm formation regardless of the concentration. In contrast, tirapazamine and tavaborole were the only drugs actively dispersing preformed biofilms. Tavaborole was the most active drug against CF pathogens other than P. aeruginosa, especially against Burkholderia cepacia and Acinetobacter baumannii, while carmofur, ebselen, and tirapazamine were particularly active against Staphylococcus aureus and B. cepacia. Electron microscopy and propidium iodide uptake assay revealed that ebselen, carmofur, and tirapazamine significantly damage cell membranes, with leakage and cytoplasm loss, by increasing membrane permeability. IMPORTANCE Antibiotic resistance makes it urgent to design new strategies for treating pulmonary infections in CF patients. The repurposing approach accelerates drug discovery and development, as the drugs' general pharmacological, pharmacokinetic, and toxicological properties are already well known. In the present study, for the first time, a high-throughput compound library screening was performed under experimental conditions relevant to CF-infected lungs. Among 3,386 drugs screened, the clinically used drugs from outside infection treatment ebselen, tirapazamine, carmofur, 5-fluorouracil, and tavaborole showed, although to different extents, anti-P. aeruginosa activity against planktonic and biofilm cells and broad-spectrum activity against other CF pathogens at concentrations not toxic to bronchial epithelial cells. The mode-of-action studies revealed ebselen, carmofur, and tirapazamine targeted the cell membrane, increasing its permeability with subsequent cell lysis. These drugs are strong candidates for repurposing for treating CF lung P. aeruginosa infections.

Dataset Information

Quantitative high-throughput drug screening identifies novel classes of drugs with anticancer activity in thyroid cancer cells: opportunities for repurposing.

Publications

Quantitative high-throughput drug screening identifies novel classes of drugs with anticancer activity in thyroid cancer cells: opportunities for repurposing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets