scholarly journals PharmacoDB: an integrative database for miningin vitrodrug screening studies

2017 ◽  
Author(s):  
Petr Smirnov ◽  
Victor Kofia ◽  
Alexander Maru ◽  
Mark Freeman ◽  
Chantal Ho ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Large Scale ◽  
Drug Response ◽  
Chemical Compounds ◽  
Integrative Analysis ◽  
Multiple Drug ◽  
List Type ◽  
Pharmacogenomic Studies

ABSTRACTRecent pharmacogenomic studies profiled large panels of cancer cell lines against hundreds of approved drugs and experimental chemical compounds. The overarching goal of these screens is to measure sensitivity of cell lines to chemical perturbation, correlate these measures to genomic features, and thereby develop novel predictors of drug response. However, leveraging this valuable data is challenging due to the lack of standards for annotating cell lines and chemical compounds, and quantifying drug response. Moreover, it has been recently shown that the complexity and complementarity of the experimental protocols used in the field result in high levels of technical and biological variation in thein vitropharmacological profiles. There is therefore a need for new tools to facilitate rigorous comparison and integrative analysis of large-scale drug screening datasets. To address this issue, we have developed PharmacoDB (pharmacodb.pmgenomics.ca), a database integrating the largest pharmacogenomic studies published to date. Here, we describe how the curation of cell line and chemical compound identifiers maximizes the overlap between datasets and how users can leverage such data to compare and extract robust drug phenotypes. PharmacoDB provides a unique resource to mine a compendium of curated pharmacogenomic datasets that are otherwise disparate and difficult to integrate.Key pointsCuration of cell line and drug identifiers in the largest pharmacogenomic studies published to dateUniform processing of drug sensitivity data to reduce heterogeneity across studiesMultiple drug response summary metrics enabling visual comparison and integrative analysis

Connecting gene expression subtypes of colorectal cancer (CRC) with cell lines and drug resistance.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14544-e14544
Author(s):  
Eva Budinska ◽  
Jenny Wilding ◽  
Vlad Calin Popovici ◽  
Edoardo Missiaglia ◽  
Arnaud Roth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Line ◽  
Clinical Significance ◽  
Cell Lines ◽  
Drug Response ◽  
Drug Sensitivity ◽  
Expression Profiles ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis

e14544 Background: We identified CRC gene expression subtypes (ASCO 2012, #3511), which associate with established parameters of outcome as well as relevant biological motifs. We now substantiate their biological and potentially clinical significance by linking them with cell line data and drug sensitivity, primarily attempting to identify models for the poor prognosis subtypes Mesenchymal and CIMP-H like (characterized by EMT/stroma and immune-associated gene modules, respectively). Methods: We analyzed gene expression profiles of 35 publicly available cell lines with sensitivity data for 82 drug compounds, and our 94 cell lines with data on sensitivity for 7 compounds and colony morphology. As in vitro, stromal and immune-associated genes loose their relevance, we trained a new classifier based on genes expressed in both systems, which identifies the subtypes in both tissue and cell cultures. Cell line subtypes were validated by comparing their enrichment for molecular markers with that of our CRC subtypes. Drug sensitivity was assessed by linking original subtypes with 92 drug response signatures (MsigDB) via gene set enrichment analysis, and by screening drug sensitivity of cell line panels against our subtypes (Kruskal-Wallis test). Results: Of the cell lines 70% could be assigned to a subtype with a probability as high as 0.95. The cell line subtypes were significantly associated with their KRAS, BRAF and MSI status and corresponded to our CRC subtypes. Interestingly, the cell lines which in matrigel created a network of undifferentiated cells were assigned to the Mesenchymal subtype. Drug response studies revealed potential sensitivity of subtypes to multiple compounds, in addition to what could be predicted based on their mutational profile (e.g. sensitivity of the CIMP-H subtype to Dasatinib, p<0.01). Conclusions: Our data support the biological and potentially clinical significance of the CRC subtypes in their association with cell line models, including results of drug sensitivity analysis. Our subtypes might not only have prognostic value but might also be predictive for response to drugs. Subtyping cell lines further substantiates their significance as relevant model for functional studies.

scholarly journals CTDPathSim: Cell line-tumor deconvoluted pathway-based similarity in the context of precision medicine in cancer *

2020 ◽  
Author(s):  
Banabithi Bose ◽  
Serdar Bozdag
Keyword(s):  
Precision Medicine ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Drug Response ◽  
Expression Profiles ◽  
Cancer Cell Lines ◽  
List Type ◽  
Primary Tumors ◽  
A Genome

ABSTRACTIn cancer research and drug development, human tumor-derived cell lines are used as popular model for cancer patients to evaluate the biological functions of genes, drug efficacy, side-effects, and drug metabolism. Using these cell lines, the functional relationship between genes and drug response and prediction of drug response based on genomic and chemical features have been studied. Knowing the drug response on the real patients, however, is a more important and challenging task. To tackle this challenge, some studies integrate data from primary tumors and cancer cell lines to find associations between cell lines and tumors. These studies, however, do not integrate multi-omics datasets to their full extent. Also, several studies rely on a genome-wide correlation-based approach between cell lines and bulk tumor samples without considering the heterogeneous cell population in bulk tumors. To address these gaps, we developed a computational pipeline, CTDPathSim, a pathway activity-based approach to compute similarity between primary tumor samples and cell lines at genetic, genomic, and epigenetic levels integrating multi-omics datasets. We utilized a deconvolution method to get cell type-specific DNA methylation and gene expression profiles and computed deconvoluted methylation and expression profiles of tumor samples. We assessed CTDPathSim by applying on breast and ovarian cancer data in The Cancer Genome Atlas (TCGA) and cancer cell lines data in the Cancer Cell Line Encyclopedia (CCLE) databases. Our results showed that highly similar sample-cell line pairs have similar drug response compared to lowly similar pairs in several FDA-approved cancer drugs, such as Paclitaxel, Vinorelbine and Mitomycin-c. CTDPathSim outperformed state-of-the-art methods in recapitulating the known drug responses between samples and cell lines. Also, CTDPathSim selected higher number of significant cell lines belonging to the same cancer types than other methods. Furthermore, our aligned cell lines to samples were found to be clinical biomarkers for patients’ survival whereas unaligned cell lines were not. Our method could guide the selection of appropriate cell lines to be more intently serve as proxy of patient tumors and could direct the pre-clinical translation of drug testing into clinical platform towards the personalized therapies. Furthermore, this study could guide the new uses for old drugs and benefits the development of new drugs in cancer treatments.CCS CONCEPTSComputational biologyGenomicsSystems biologyBioinformaticsGeneticsACM Reference formatBanabithi Bose, Serdar Bozdag. 2020. CTDPathSim: Cell line-tumor deconvoluted pathway-based similarity in the context of precision medicine in cancer.

scholarly journals Karyotypic divergence confounds cellular phenotypes in large pharmacogenomic studies

2019 ◽  
Author(s):  
Rene Quevedo ◽  
Nehme El-Hachem ◽  
Petr Smirnov ◽  
Zhaleh Safikhani ◽  
Trevor J. Pugh ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Copy Number ◽  
Drug Response ◽  
Drug Sensitivity ◽  
Genomic Diversity ◽  
Sensitivity Data ◽  
Cellular Phenotypes ◽  
The Impact ◽  
Pharmacogenomic Studies

ABSTRACTBackgroundSomatic copy-number alterations that affect large genomic regions are a major source of genomic diversity in cancer and can impact cellular phenotypes. Clonal heterogeneity within cancer cell lines can affect phenotypic presentation, including drug response.MethodsWe aggregated and analyzed SNP and copy number profiles from six pharmacogenomic datasets encompassing 1,691 cell lines screened for 13 molecules. To look for sources of genotype and karyotype discordances, we compared SNP genotypes and segmental copy-ratios across 5 kb genomic bins. To assess the impact of genomic discordances on pharmacogenomic studies, we assessed gene expression and drug sensitivity data for compared discordant and concordant lines.ResultsWe found 6/1,378 (0.4%) cell lines profiled in two studies to be discordant in both genotypic and karyotypic identity, 51 (3.7%) discordant in genotype, 97 (7.0%) discordant in karyotype, and 125 (9.1%) potential misidentifications. We highlight cell lines REH, NCI-H23 and PSN1 as having drug response discordances that may hinge on divergent copy-number qConclusionsOur study highlights the low level of misidentification as evidence of effective cell line authentication standards in recent pharmacogenomic studies. However, the proclivity of cell lines to acquire somatic copy-number variants can alter the cellular phenotype, resulting in a biological and predictable effects on drug sensitivity. These findings highlight the need for verification of cell line copy number profiles to inform interpretation of drug sensitivity data in biomedical studies.

scholarly journals Global computational alignment of tumor and cell line transcriptional profiles

2020 ◽  
Author(s):  
Allison Warren ◽  
Andrew Jones ◽  
Tsukasa Shibue ◽  
William C. Hahn ◽  
Jesse S. Boehm ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Large Scale ◽  
Tumor Cell Line ◽  
Distinct Group ◽  
Cancer Type ◽  
Transcriptional Profiles ◽  
Tumor Subtypes ◽  
Tumor Expression

AbstractCell lines are key tools for preclinical cancer research, but it remains unclear how well they represent patient tumor samples. Identifying cell line models that best represent the features of particular tumor samples, as well as tumor types that lack in vitro model representation, remain important challenges. Gene expression has been shown to provide rich information that can be used to identify tumor subtypes, as well as predict the genetic dependencies and chemical vulnerabilities of cell lines. However, direct comparisons of tumor and cell line transcriptional profiles are complicated by systematic differences, such as the presence of immune and stromal cells in tumor samples and differences in the cancer-type composition of cell line and tumor expression datasets. To address these challenges, we developed an unsupervised alignment method (Celligner) and applied it to integrate several large-scale cell line and tumor RNA-Seq datasets. While our method aligns the majority of cell lines with tumor samples of the same cancer type, it also reveals large differences in tumor/cell line similarity across disease types. Furthermore, Celligner identifies a distinct group of several hundred cell lines from diverse lineages that present a more mesenchymal and undifferentiated transcriptional state and which exhibit distinct chemical and genetic dependencies. This method could thus be used to guide the selection of cell lines that more closely resemble patient tumors and improve the clinical translation of insights gained from cell line models.

Generation of a Pre-Leukemic, Transplantable Cell Line from the AML-Associated NUP98-TOP1 Fusion Gene as a New Model To Test Potential Collaborating Genes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1969-1969
Author(s):  
Rhonna M. Gurevich ◽  
Peter D. Aplan ◽  
R. Keith Humphries
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Topoisomerase I ◽  
Large Scale ◽  
Fusion Gene ◽  
Fusion Partner ◽  
Short Term ◽  
Transplantable Cell ◽  
Long Latency

Abstract Over 15 distinct chromosomal translocations have been documented in human leukemias that involve rearrangement of the nucleoporin gene, NUP98. While most NUP98 fusion partners are HOX transcription factors, the remaining 7 have no obvious common unifying function or unique role in hematopoiesis. The translocation t(11;20) identified the novel NUP98 fusion partner Topoisomerase I (TOP1), a catalytic enzyme known for its role in relaxing supercoiled DNA. We recently demonstrated that over-expression of NUP98-TOP1 induces a lethal, transplantable AML in a murine bone marrow (BM) transplantation model (Gurevich et al, Blood 2004). To further explore the mechanistic process of leukemic transformation we sought to establish BM cell lines that retain the preleukemic-inducing properties of NUP98-TOP1. Murine BM was transduced with GFP-linked NUP98-TOP1 retrovirus. Following 4 weeks of culture, there was a striking out-growth of GFP+ cells (expansion of 1% to >80% GFP+ cells) and generation of poly-clonal cell lines (herein called NT 12.1 and NT 12.2) exhibiting features of primitive cells (blast-like morphology, lin−/lo, increased levels of c-Kit, Sca-1 and CD34). NT cell lines had limited differentiation ability when plated in GM-CSF, G-CSF or M-CSF but in methylcellulose colony assays generated large granulo-monocytic colonies at high frequency (1 in 12) when plated in IL-3, IL-6, SCF and EPO. Strikingly, NT cell lines demonstrated significant levels of short-term in vivo repopulating ability when transplanted into lethally irradiated recipients. Transplant doses of 104-106 cells yielded >50% engraftment at 1 month post transplant (tx) (54±13% GFP+ WBC; n=12) which diminished to levels of <20% by 2 months. The frequency of cells with repopulating potential was estimated at 1 in 1609 following limit dilution assay which yielded repopulation of 3 of 4 recipients 1 month post-tx (range; 5–46%). While the level of engraftment diminished in NT 12.1 mice, two NT 12.2 mice developed fatal MPD/AML after a latency of 103 and 166 days. Thus these NUP98-TOP1 cell lines demonstrate a differentiation block in vitro, high level short term repopulating capacity and the potential to give rise to AML with a long latency that is consistent with a preleukemic phenotype. These lines now provide a novel platform to test candidate genes for their ability to co-operate with NUP98-TOP1 to induce leukemia. As an initial candidate, we tested the collaborating potential of Meis1, a HOX co-factor known to co-operate with several NUP98-HOX fusions to induce a rapid leukemia and may thus represent a common collaborating gene in NUP98 associated leukemias. When a representative cell line (NT12.2) was infected with a YFP-linked Meis1 retrovirus and transplanted into mice, the mice contained only GFP+/YFP+ circulating WBC by 1 months post-tx. However, despite co-expression of both genes in all transplanted mice, there was no apparent acceleration of induction of AML with 5 of 6 recipients succumbing to leukemia by 9 months post-tx, (median survival 164 days; range 101–193). This long latency argues that Meis1 does not collaborate with NUP98-TOP1 to induce leukemia and that NUP98-TOP1 has distinct mechanisms of leukemogenesis compared to NUP98-HOX fusions. These novel pre-leukemic, transplantable cell lines generated by NUP98-TOP1 will facilitate further large scale screens for potential cooperative genes and delineation of the mechanistic basis of NUP98-TOP1 induced transformation.

scholarly journals Kernel multitask regression for toxicogenetics

2017 ◽  
Author(s):  
Elsa Bernard ◽  
Yunlong Jiao ◽  
Erwan Scornet ◽  
Veronique Stoven ◽  
Thomas Walter ◽  
...  
Keyword(s):  
Machine Learning ◽  
Cell Line ◽  
Cell Lines ◽  
High Throughput ◽  
State Of The Art ◽  
Chemical Compounds ◽  
Molecular Compounds ◽  
The Way

AbstractThe development of high-throughput in vitro assays to study quantitatively the toxicity of chemical compounds on genetically characterized human-derived cell lines paves the way to predictive toxicogenetics, where one would be able to predict the toxicity of any particular compound on any particular individual. In this paper we present a machine learning-based approach for that purpose, kernel multitask regression (KMR), which combines chemical characterizations of molecular compounds with genetic and transcriptomic characterizations of cell lines to predict the toxicity of a given compound on a given cell line. We demonstrate the relevance of the method on the recent DREAM8 Toxicogenetics challenge, where it ranked among the best state-of-the-art models, and discuss the importance of choosing good descriptors for cell lines and chemicals.

ANTITUMOR EFFECT OF SUNITINIB AND BORTEZOMIB ON BREAST CANCER CELL LINE IN VITRO

2017 ◽  
Vol 63 (1) ◽  
pp. 141-145
Author(s):  
Yuliya Khochenkova ◽  
Eliso Solomko ◽  
Oksana Ryabaya ◽  
Yevgeniya Stepanova ◽  
Dmitriy Khochenkov
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Antitumor Effect ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Actual Problem

The discovery for effective combinations of anticancer drugs for treatment for breast cancer is the actual problem in the experimental chemotherapy. In this paper we conducted a study of antitumor effect of the combination of sunitinib and bortezomib against MDA-MB-231 and SKBR-3 breast cancer cell lines in vitro. We found that bortezomib in non-toxic concentrations can potentiate the antitumor activity of sunitinib. MDA-MB-231 cell line has showed great sensitivity to the combination of bortezomib and sunitinib in vitro. Bortezomib and sunitinib caused reduced expression of receptor tyrosine kinases VEGFR1, VEGFR2, PDGFRa, PDGFRß and c-Kit on HER2- and HER2+ breast cancer cell lines

Design, Synthesis, Molecular Docking, and Anticancer Evaluation of Pyrazole Linked Pyrazoline Derivatives with Carbothioamide Tail as EGFR Kinase Inhibitors

2020 ◽  
Vol 21 (1) ◽  
pp. 42-60
Author(s):  
Farah Nawaz ◽  
Ozair Alam ◽  
Ahmad Perwez ◽  
Moshahid A. Rizvi ◽  
Mohd. Javed Naim ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Cancer Cell Lines ◽  
Kinase Assay ◽  
Cervix Uteri ◽  
Egfr Kinase

Background: The Epidermal Growth Factor Receptor (known as EGFR) induces cell differentiation and proliferation upon activation through the binding of its ligands. Since EGFR is thought to be involved in the development of cancer, the identification of new target inhibitors is the most viable approach, which recently gained momentum as a potential anticancer therapy. Objective: To assess various pyrazole linked pyrazoline derivatives with carbothioamide for EGFR kinase inhibitory as well as anti-proliferative activity against human cancer cell lines viz. A549 (non-small cell lung tumor), MCF-7 (breast cancer cell line), SiHa (cancerous tissues of the cervix uteri), and HCT-116 (colon cancer cell line). Methods: In vitro EGFR kinase assay, in vitro MTT assay, Lactate dehydrogenase release, nuclear staining (DAPI), and flow cytometry cell analysis. Results: Compounds 6h and 6j inhibited EGFR kinase at concentrations of 1.66μM and 1.9μM, respectively. Furthermore, compounds 6h and 6j showed the most potent anti-proliferative results against the A549 KRAS mutation cell line (IC50 = 9.3 & 10.2μM). Through DAPI staining and phase contrast microscopy, it was established that compounds 6h and 6j also induced apoptotic activity in A549 cells. This activity was further confirmed by FACS using Annexin-V-FITC and Propidium Iodide (PI) labeling. Molecular docking studies performed on 6h and 6j suggested that the compounds can bind to the hinge region of ATP binding site of EGFR tyrosine kinase in a similar pose as that of the standard drug gefitinib. Conclusion: The potential anticancer activity of compounds 6h and 6j was confirmed and need further exploration in cancer cell lines of different tissue origin and signaling pathways, as well as in animal models of cancer development.

Survival and Function of Fibroblasts Stored as Stock Cultures at a Non-freezing Temperature

1993 ◽  
Vol 21 (2) ◽  
pp. 206-209
Author(s):  
Anders H. G. Andrén ◽  
Anders P. Wieslander
Keyword(s):  
Cell Growth ◽  
Cell Line ◽  
Cell Lines ◽  
Fibroblast Cell ◽  
Freezing Temperature ◽  
Mouse Fibroblast ◽  
Toxic Response ◽  
Normal Manner ◽  
And Function

Cytotoxicity, measured as inhibition of cell growth of cultured cell lines, is a widely used method for testing the safety of biomaterials and chemicals. One major technical disadvantage with this method is the continuous routine maintenance of the cell lines. We decided to investigate the possibility of storing stock cultures of fibroblasts (L-929) in an ordinary refrigerator as a means of reducing the routine workload. Stock cultures of the mouse fibroblast cell line L-929 were prepared in plastic vials with Eagle's minimum essential medium. The vials were stored in a refrigerator at 4–10°C for periods of 7–31 days. The condition of the cells after storage was determined as cell viability, cell growth and the toxic response to acrylamide, measured as cell growth inhibition. We found that the L-929 cell line can be stored for 2–3, weeks with a viabilty > 90% and a cell growth of about 95%, compared to L-929 cells grown and subcultured in the normal manner. The results also show that the toxic response to acrylamide, using refrigerator stored L-929 cells, corresponds to that of control L-929 cells. We concluded that it is possible to store L-929 cells in a refrigerator for periods of up to 3 weeks and still use the cells for in vitro cytotoxic assays.

scholarly journals Tissue type-specific expression of intermediate filament proteins in a cultured epithelial cell line from bovine mammary gland

1983 ◽  
Vol 96 (1) ◽  
pp. 37-50 ◽  
Author(s):  
E Schmid ◽  
DL Schiller ◽  
C Grund ◽  
J Stadler ◽  
WW Franke
Keyword(s):  
Mammary Gland ◽  
Epithelial Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Intermediate Filament ◽  
Striking Difference ◽  
Intermediate Filament Proteins ◽  
Cell Clones ◽  
Vimentin Filaments

Different clonal cell lines have been isolated from cultures of mammary gland epithelium of lactating cow's udder and have been grown in culture media containing high concentrations of hydrocortisone, insulin, and prolactin. These cell (BMGE+H), which grow in monolayers of typical epithelial appearance, are not tightly packed, but leave intercellular spaces spanned by desmosomal bridges. The cells contain extended arrays of cytokeratin fibrils, arranged in bundles attached to desmosomes. Gel electophoresis show that they synthesize cytokeratins similar, if not identical, to those found in bovine epidermis and udder, including two large (mol wt 58,500 and 59,000) and basic (pH range: 7-8) and two small (mol wt 45,500 and 50,000) and acidic (pH 5.32 and 5.36) components that also occur in phosphorylated forms. Two further cytokeratins of mol wts 44,000 (approximately pH 5.7) and 53,000 (pH 6.3) are detected as minor cytokeratins in some cell clones. BMGE+H cells do not produce vimentin filaments as determined by immunofluorescence microscopy and gel electrophoresis. By contrast, BMGE-H cells, which have emerged from the same original culture but have been grown without hormones added, are not only morphologically different, but also contain vimentin filaments and a different set of cytokeratins, the most striking difference being the absence of the two acidic cytokeratins of mol wt 50,000 and 45,500. Cells of the BMGE+H line are characterized by an unusual epithelial morphology and represent the first example of a nonmalignant permanent cell line in vitro that produces cytokeratin but not vimentin filaments. The results show that (a) tissue-specific patterns of intermediate filament expression can be maintained in permanent epithelial cell lines in culture, at least under certain growth conditions; (b) loss of expression of relatively large, basic cytokeratins is not an inevitable consequence of growth of epithelial cells in vitro. Our results further show that, during culturing, different cell clones with different cytoskeletal composition can emerge from the same cell population and suggest that the presence of certain hormones may have an influence on the expression of intermediate filament proteins.

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