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High-content, high-throughput screening for the identification of cytotoxic compounds based on cell morphology and cell proliferation markers. | LitMetric

High-content, high-throughput screening for the identification of cytotoxic compounds based on cell morphology and cell proliferation markers.

PLoS One

BioScreening Technology Group, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds, United Kingdom ; Section of Ophthalmology and Neuroscience, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds, United Kingdom ; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.

Published: September 2014

AI Article Synopsis

Article Abstract

Toxicity is a major cause of failure in drug discovery and development, and whilst robust toxicological testing occurs, efficiency could be improved if compounds with cytotoxic characteristics were identified during primary compound screening. The use of high-content imaging in primary screening is becoming more widespread, and by utilising phenotypic approaches it should be possible to incorporate cytotoxicity counter-screens into primary screens. Here we present a novel phenotypic assay that can be used as a counter-screen to identify compounds with adverse cellular effects. This assay has been developed using U2OS cells, the PerkinElmer Operetta high-content/high-throughput imaging system and Columbus image analysis software. In Columbus, algorithms were devised to identify changes in nuclear morphology, cell shape and proliferation using DAPI, TOTO-3 and phosphohistone H3 staining, respectively. The algorithms were developed and tested on cells treated with doxorubicin, taxol and nocodazole. The assay was then used to screen a novel, chemical library, rich in natural product-like molecules of over 300 compounds, 13.6% of which were identified as having adverse cellular effects. This assay provides a relatively cheap and rapid approach for identifying compounds with adverse cellular effects during screening assays, potentially reducing compound rejection due to toxicity in subsequent in vitro and in vivo assays.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914966PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088338PLOS

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