Analysis of PARP inhibitor toxicity by multidimensional fluorescence microscopy reveals mechanisms of sensitivity and resistance

Exploiting the full potential of anti-cancer drugs necessitates a detailed understanding of their cytotoxic effects. While standard omics approaches are limited to cell population averages, emerging single cell techniques currently lack throughput and are not applicable for compound screens. Here, w...

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Vydáno v:	Nature communications Ročník 9; číslo 1; s. 2678 - 16
Hlavní autoři:	Michelena, Jone, Lezaja, Aleksandra, Teloni, Federico, Schmid, Thomas, Imhof, Ralph, Altmeyer, Matthias
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 11.07.2018 Nature Publishing Group Nature Portfolio
Témata:	14 49 631/1647/245/2225 631/337/1427 631/80/2373 631/80/641/151 96 96/63 Cancer Cell cycle Cell Cycle - drug effects Cell Cycle - genetics Cell Line Cell Line, Tumor Cell Survival - drug effects Cell Survival - genetics Cytotoxicity Deoxyribonucleic acid DNA DNA Damage DNA Repair Drug Resistance - drug effects Drug Resistance - genetics Fluorescence Fluorescence microscopy Humanities and Social Sciences Humans Hypersensitivity Microscopy Microscopy, Fluorescence - methods multidisciplinary Phthalazines - pharmacology Piperazines - pharmacology Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerases - genetics Poly(ADP-ribose) Polymerases - metabolism RNA Interference Science Science (multidisciplinary) Synergism Targeted cancer therapy Time-Lapse Imaging - methods Toxicity Trapping
ISSN:	2041-1723, 2041-1723
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Shrnutí:	Exploiting the full potential of anti-cancer drugs necessitates a detailed understanding of their cytotoxic effects. While standard omics approaches are limited to cell population averages, emerging single cell techniques currently lack throughput and are not applicable for compound screens. Here, we employed a versatile and sensitive high-content microscopy-based approach to overcome these limitations and quantify multiple parameters of cytotoxicity at the single cell level and in a cell cycle resolved manner. Applied to PARP inhibitors (PARPi) this approach revealed an S-phase-specific DNA damage response after only 15 min, quantitatively differentiated responses to several clinically important PARPi, allowed for cell cycle resolved analyses of PARP trapping, and predicted conditions of PARPi hypersensitivity and resistance. The approach illuminates cellular mechanisms of drug synergism and, through a targeted multivariate screen, could identify a functional interaction between PARPi olaparib and NEDD8/SCF inhibition, which we show is dependent on PARP1 and linked to PARP1 trapping. Methods to study anti-cancer drugs cytotoxicity are often low throughput and rely on population average. Here the authors present an automated image-based cytometry method to quantify multiple cytotoxicity parameters in single cells, and use it to study the effect of PARP inhibitors in cancer cells.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-018-05031-9