Early safety assessment using cellular systems biology yields insights into mechanisms of action

Journal of Biomolecular Screening
Kenneth A GiulianoPatricia A Johnston

Abstract

The integration of high-content screening (HCS) readers with organ-specific cell models, panels of functional biomarkers, and advanced informatics is a powerful approach to identifying the toxic liabilities of compounds early in the development process and forms the basis of "early safety assessment." This cellular systems biology (CSB) approach (CellCiphr profile) has been used to integrate rodent and human cellular hepatic models with panels of functional biomarkers measured at multiple time points to profile both the potency and specificity of the cellular toxicological response. These profiles also provide initial insights on the mechanism of the toxic response. The authors describe here mechanistic assay profiles designed to further dissect the toxic mechanisms of action and elucidate subtle effects apparent in subpopulations of cells. They measured 8 key mechanisms of toxicity with multiple biomarker feature measurements made simultaneously in populations of living primary hepatocytes and HepG2 cells. Mining the cell population response from these mechanistic profiles revealed the concentration dependence and nature of the heterogeneity of the response, as well as relationships between the functional responses. These more...Continue Reading

References

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Citations

Feb 26, 2014·Stem Cell Research & Therapy·Abhinav BhushanD Lansing Taylor
Feb 20, 2014·Assay and Drug Development Technologies·Adam T Szafran, Michael A Mancini
Apr 26, 2011·Toxicology in Vitro : an International Journal Published in Association with BIBRA·K TilmantF A Atienzar
May 22, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Richard JudsonRussell S Thomas
Oct 24, 2007·PLoS Genetics·Axel ViselGregor Eichele
Jul 24, 2015·Experimental Biology and Medicine·Lawrence A VernettiD Lansing Taylor
May 21, 2015·Experimental Biology and Medicine·Nina SenutovitchD Lansing Taylor
Jul 20, 2010·Journal of Biomolecular Screening·D Lansing Taylor
Jun 19, 2012·Journal of Biomolecular Screening·Danli L TowneVivek C Abraham
Jan 16, 2019·Journal of Chemical Information and Modeling·David A DreierChristopher J Martyniuk
Aug 30, 2011·Bioorganic Chemistry·Phillip A Schwartz, Brion W Murray

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Methods Mentioned

BETA
dissect

Software Mentioned

CellCiphr

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