Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions

Schmidt, Linnéa; Kling, Teresia; Monsefi, Naser; Olsson, Maja; Hansson, Caroline; Baskaran, Sathishkumar; Lundgren, Bo; Märtens, Ulf; Häggblad, Maria; Westermark, Bengt; Nilsson, Karin; Uhrbom, Lene; Karlsson-Lindahl, Linda; Gerlee, Philip; Nelander, Sven

doi:10.1093/neuonc/not111

Cited by 20 publications

(18 citation statements)

References 35 publications

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“…All ethical, legal and practical matters regarding sharing the cell lines are in place. A number of the HGCC cell lines have already been used in different types of investigations ranging from basic understanding of GBM biology ( Savary et al, 2013 , Babateen et al, 2015 , Wee et al, 2014 ), drug screening ( Schmidt et al, 2013 ), drug discovery ( Kitambi et al, 2014 ) and development of vectors for gene therapy ( Yu et al, 2013 ). The HGCC resource enables accurate cell-based modeling of GBM and is connected with a database ( www.hgcc.se ), which provides current molecular, phenotypic and clinical data on each cell line in a searchable fashion ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…This information, along with clinical variables, is also available online ( www.hgcc.se ). The utility of this database is reflected in the fact that several of these cell lines have already been shared and used to discover a novel potent candidate drug for treatment of GBM ( Kitambi et al, 2014 ), as well as in a number of other studies ( Wee et al, 2014 , Babateen et al, 2015 , Schmidt et al, 2013 , Savary et al, 2013 , Yu et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes

et al. 2015

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Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called glioma stem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional subtypes. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes

et al. 2015

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“…This framework provides a well‐established notion of estimating significance when only small numbers of replicates are present (e.g. Segre et al 2005; Lehár et al 2007; Schmidt et al 2013). Moreover, the Bliss framework is easy to understand and implement, providing straightforward generalisations when studying higher order (three or more) stressor interactions (See Supporting Information, and Tekin et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Using a newly introduced framework to measure ecological stressor interactions

et al. 2020

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Understanding how stressors combine to affect population abundances and trajectories is a fundamental ecological problem with increasingly important implications worldwide. Generalisations about interactions among stressors are challenging due to different categorisation methods and how stressors vary across species and systems. Here, we propose using a newly introduced framework to analyse data from the last 25 years on ecological stressor interactions, for example combined effects of temperature, salinity and nutrients on population survival and growth. We contrast our results with the most commonly used existing methodanalysis of variance (ANOVA)and show that ANOVA assumptions are often violated and have inherent limitations for detecting interactions. Moreover, we argue that rescalingexamining relative rather than absolute responsesis critical for ensuring that any interaction measure is independent of the strength of single-stressor effects. In contrast, non-rescaled measureslike ANOVAfind fewer interactions when single-stressor effects are weak. After reexamining 840 two-stressor combinations, we conclude that antagonism and additivity are the most frequent interaction types, in strong contrast to previous reports that synergy dominates yet supportive of more recent studies that find more antagonism. Consequently, measuring and reassessing the frequency of stressor interaction types is imperative for a better understanding of how stressors affect populations.

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“…Given the potent activation of hCAR and induction of drug metabolizing enzymes, rimcazole will need to be thoroughly studied in vitro and/or in vivo for drugdrug interactions. In a study by Schmidt et al, rimcazole had significant synergistic interactions between different compounds, where rimcazole plus sertraline was described as the most robust combination when studying co-treatments for therapeutic use against glioblastoma multiforme, the most aggressive tumor in an adult brain (Schmidt et al, 2013). Further follow-up studies should, therefore, also be performed in the future to determine rimcazole's therapeutic effect, if any, involving the hCAR pathway.…”

Section: Discussionmentioning

confidence: 99%

Identification of Modulators That Activate the Constitutive Androstane Receptor From the Tox21 10K Compound Library

Lynch

Mackowiak

Huang

et al. 2018

Toxicological Sciences

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The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor involved in all phases of drug metabolism and disposition. However, recently it’s been implicated in energy metabolism, tumor progression, and cancer therapy as well. It is, therefore, important to identify compounds that induce human CAR (hCAR) activation to predict drug-drug interactions and potential therapeutic usage. In this study, we screen the Tox21 10,000 compound collection to characterize hCAR activators. A potential novel structural cluster of compounds was identified, which included nitazoxanide and tenonitrozole, whereas known structural clusters, such as flavones and prazoles, were also detected. Four compounds, neticonazole, diphenamid, phenothrin, and rimcazole, have been identified as novel hCAR activators, one of which, rimcazole, shows potential selectivity toward hCAR over its sister receptor, the pregnane X receptor (PXR). All 4 compounds translocated hCAR from the cytoplasm into the nucleus demonstrating the first step to CAR activation. Profiling these compounds as hCAR activators would enable an estimation of drug-drug interactions, as well as identify prospective therapeutically beneficial drugs.

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Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions

Abstract: We identify novel candidate drug pairs for GBM and suggest possibilities to prospectively use transcriptional biomarkers to predict drug interactions in individual cases.

Cited by 20 publications

References 35 publications

The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes

The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes

Using a newly introduced framework to measure ecological stressor interactions

Identification of Modulators That Activate the Constitutive Androstane Receptor From the Tox21 10K Compound Library

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