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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [ATAC-Seq]

ABSTRACT: More than 500 kinases are implicated in the control of virtually every cellular process in mammals and deregulation of their activity is causally linked to diseases ranging from cancer to inflammatory and degenerative disorders. In the last three decades, massive worldwide efforts led to the approval of 62 clinical kinase inhibitors (CKI), with hundreds of additional molecules in various stages of pre-clinical or clinical development. In addition to the intended target(s), small molecule CKI commonly inhibit multiple additional kinases, resulting in both enhanced clinical effects and undesired side effects that are largely unpredictable based on in vitro selectivity profiling. To complement current CKI profiling methods, we set out a novel experimental and analytical approach grounded on the use of chromatin modifications as unbiased and information-rich readouts of the functional effects of CKI on macrophage activation, a complex biological response of biomedical relevance. This approach allowed us to characterize and dissect the distinctive behaviors of CKI with identical intended targets as well as to discover undescribed activities of CKI on macrophage activation programs.

ORGANISM(S): Mus musculus

PROVIDER: GSE218966 | GEO | 2024/04/16

REPOSITORIES: GEO

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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [ChIP-Seq]

Project description:More than 500 kinases are implicated in the control of virtually every cellular process in mammals and deregulation of their activity is causally linked to diseases ranging from cancer to inflammatory and degenerative disorders. In the last three decades, massive worldwide efforts led to the approval of 62 clinical kinase inhibitors (CKI), with hundreds of additional molecules in various stages of pre-clinical or clinical development. In addition to the intended target(s), small molecule CKI commonly inhibit multiple additional kinases, resulting in both enhanced clinical effects and undesired side effects that are largely unpredictable based on in vitro selectivity profiling. To complement current CKI profiling methods, we set out a novel experimental and analytical approach grounded on the use of chromatin modifications as unbiased and information-rich readouts of the functional effects of CKI on macrophage activation, a complex biological response of biomedical relevance. This approach allowed us to characterize and dissect the distinctive behaviors of CKI with identical intended targets as well as to discover undescribed activities of CKI on macrophage activation programs.

2024-04-16 | GSE219239 | GEO

Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [RNA-Seq]

2024-04-16 | GSE219229 | GEO

Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [Chromatin associated RNA-seq]

2024-04-16 | GSE218968 | GEO

A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism

Project description:To elucidate the effect of senescence in mouse colorectal tumor, the transcriptome of enterocytes from CKI alpha deletion mutants (CKI alpha KO), CKI alpha/p53 double deletion mutants (CKI alpha/p53 DKO) and CKI alpha heterozygous mice (CKI alpha Het) were determined by RNAseq.

2013-06-12 | E-MTAB-1683 | biostudies-arrayexpress

Understanding the Mechanistic Contribution of Herbal Extracts in Compound Kushen Injection with Transcriptome Analysis

Project description:Herbal compatibility is the knowledge of which herbs to combine in traditional Chinese medicine (TCM) formulations. The lack of understanding of herbal compatibility is one of the key problems for the application and popularization of TCM in western society. Because of the chemical complexity of herbal medicines, it is simpler to begin to conduct compatibility research based on herbs rather than component plant secondary metabolites. We have used transcriptome analysis to explore the effects and interactions of two plant extracts (Kushen and Baituling) combined in Compound Kushen Injection (CKI). Based on shared chemical compounds and in vitro cytotoxicity comparisons, we found that both the major compounds in CKI, and the cytotoxicity effects of CKI were mainly derived from the extract of Kushen (Sophorae flavescentis). We generated and analyzed transcriptome data from MDA-MB-231 cells treated with single-herb extracts or CKI and results showed that Kushen contributed to the perturbation of the majority of cytotoxicity/cancer related pathways in CKI such as cell cycle and DNA replication. We also found that Baituling (Heterosmilax yunnanensis Gagnep) could not only enhance the cytotoxic effects of Kushen in CKI, but also activate immune-related pathways. Our analyses predicted that IL-1[beta] gene expression was upregulated by Baituling in CKI and we confirmed that IL-1[beta] protein expression was increased using an ELISA assay. Altogether, these findings help to explain the rationale for combining Kushen and Baituling in CKI, and show that transcriptome analysis using single herb extracts is an effective method for understanding herbal compatibility in TCM.

2019-08-20 | GSE130358 | GEO

The Effect of Compound Kushen Injection on Cancer Cells: Integrated Identification of Candidate Molecular Mechanisms

Project description:Compound Kushen Injection (CKI) is a TCM fomula has been in use in hospitals in China for over twenty years for the integrated treatment of cancer.There is little evidence based medicine supporting such complex mixture. Because TCM preparations are often combinations of multiple herbs containing hundreds of compounds, they have been difficult to study. The development of high throughput -omics methods has allowed better characterization of TCM. We have applied high-throughput transcriptome data in two additional cancer cell lines and integrated our differential expression results across cell lines to identify a reduced set of differentially expressed (DE) candidate genes as well as a reproducible set of candidate pathways that are perturbed by CKI. In our results,CKI induced cell-cycle arrest and apoptosis. We identified 363 core candidate genes that were associated with cell cycle, apoptosis, DNA replication/repair and various cancer pathways. Of these, 7 are known to be clinically relevant to cancer diagnosis or therapy and 14 are cell cycle regulators, and most of these 21 candidates are downregulated by CKI. Comparison of our core candidate genes to a database of plant medicinal compounds and their effects on gene expression identified one-to-one, one-to-many and many-to-many regulatory relationships between compounds in CKI and DE genes.By identifying a number of promising candidate pathways and genes associated with CKI based on our transcriptome based analysis, we have shown this type of approach is useful for the systematic analysis of molecular changes resulting from complex mixtures of bioactives in the context of cancer therapy.

2020-08-05 | GSE124715 | GEO

A new strategy for identifying mechanisms of drug-drug interaction using transcriptome analysis: Compound Kushen injection as a proof of principle

Project description:Drug-drug interactions (DDIs), especially with herbal medicines, are complex, making it difficult to identify potential molecular mechanisms and targets. We introduce a workflow to carry out DDI research using transcriptome analysis and interactions of a complex herbal mixture, Compound Kushen Injection (CKI), with cancer chemotherapy drugs, as a proof of principle. Using CKI combined with doxorubicin or 5-Fu on cancer cells as a model, we found that CKI enhanced the cytotoxic effects of doxorubicin on A431 cells while protecting MDA-MB-231 cells treated with 5-Fu. We generated and analysed transcriptome data from cells treated with single treatments or combined treatments and our analysis showed that opposite directions of regulation for pathways related to DNA synthesis and metabolism appeared to be the main reason for different effects of CKI when used in combination with chemotherapy drugs . We also found that pathways related to organic biosynthetic and metabolic processes might be potential targets for CKI when interacting with doxorubicin and 5-Fu. Through co-expression analysis correlated with phenotype results, we selected the MYD88 gene as a candidate major regulator for validation as a proof of concept for our approach. Inhibition of MYD88 reduced antagonistic cytotoxic effects between CKI and 5-Fu, indicating that MYD88 is an important gene in the DDI mechanism between CKI and chemotherapy drugs. These findings demonstrate that our pipeline is effective for the application of transcriptome analysis to the study of DDIs in order to identify candidate mechanisms and potential targets.

2019-08-20 | GSE130359 | GEO

Compound kushen injection and YFSJ reduce gefitinib resistance in gefitinib resistant lung cancer cell lines

Project description:Compound Kushen Injection (CKI) has been used in clinics for nearly 20 years to treat different kinds of cancers. In this study, we found that CKI inhibited gefitinib resistant cell line proliferation, reduced drug resistance and improved anti-cancer effects when associated with gefitinib in a dose-dependent fashion. We also identified candidate CKI associated molecular mechanisms that might reduce drug resistance using transcriptome analysis methods, including gene differential expression analysis and pathway over-representation analysis. Multiple pathways were perturbed and the PI3K/AKT/MTOR and autophagy pathways were identified as the potential primary target pathways of CKI in this context. We also investigated the molecular mechanisms of another TCM, Yifei-Sanjie Wan (YFSJ) on reducing gefitinib resistance using transcriptome analysis.

2022-01-15 | GSE125933 | GEO

Fractional Deletion of Compound Kushen Injection Indicates Cytokine Signaling Pathways are Critical for its Perturbation of the Cell Cycle

Project description:We have used computational and experimental biology approaches to identify candidate mechanisms of action of a traditional Chinese medicine; Compound Kushen Injection (CKI), in a breast cancer cell line in which CKI has been shown to cause apoptosis. Because CKI is a complex mixture of plant secondary metabolites, we used a high-performance liquid chromatography (HPLC) fractionation and reconstitution approach to define chemical fractions required for CKI to induce apoptosis in MDA-MB-231 cells. Our initial fractionation separated major from minor compounds, and showed that the major compounds accounted for little of the activity of CKI. By systematically perturbing the major compounds in CKI we found that removal of no single major compound could alter the effect of CKI on cell viability and apoptosis. However, simultaneous removal of two major compounds identified oxymatrine and oxysophocarpine as critical compounds with respect to CKI activity. We then used RNA sequencing and transcriptome analysis to correlate compound removal with gene expression and phenotype data. We determined that many compounds in CKI are required for its effectiveness in triggering apoptosis but that significant modulation of its activity is conferred by a small number of compounds. In conclusion, CKI may be typical of many plant based extracts that contain many compounds in that no single compound is responsible for all of the bioactivity of the mixture and that many compounds interact in a complex fashion to influence a network containing many targets.

2019-05-29 | GSE125743 | GEO

Identification Of Candidate Anti-Cancer Molecular Mechanisms Of Compound Kushen Injection Using Functional Genomics

Project description:Compound Kushen Injection (CKI) has been clinically used in China for over 15 years to treat various types of solid tumours. However, because such Traditional Chinese Medicine (TCM) preparations are complex mixtures of plant secondary metabolites, it is essential to explore their underlying molecular mechanisms in a systematic fashion. We have used the MCF-7 breast cancer cell line as an initial in vitro model to identify CKI induced changes in gene expression. Cells were treated with CKI for 24 and 48 hours at two concentrations (1.0 and 2.0 mg/mL), and 5-Fluorouracil (5-FU) was used to treat cells as a positive control. Cell proliferation and apoptosis activity were measured with XTT and Caspase-3 assays respectively. Transcriptome data of cells treated with CKI or 5-FU for 24 and 48 hours were acquired using high-throughput Illumina RNA-seq technology. In this report we show that CKI inhibited MCF-7 cell proliferation and induced apoptosis in a dose-dependent fashion. We integrated and applied a series of transcriptome analysis methods, including gene differential expression analysis, pathway over-representation analysis, de novo identification of long non-coding RNAs (lncRNA) as well as co-expression network reconstruction, to identify candidate anti-cancer molecular mechanisms of CKI. Multiple pathways were perturbed and the cell cycle was identified as the potential primary target pathway of CKI in MCF-7 cells. CKI may also induce apoptosis in MCF-7 cells via a p53 independent mechanism. In addition, we identified novel lncRNAs and showed that many of them might be expressed as a response to CKI treatment. Overall, we have comprehensively investigated the utility of transcriptome analysis with high-throughput sequencing to characterise the molecular response of cancer cells to a TCM drug, and provided a practical guideline for future molecular studies of TCM.

2016-09-14 | GSE78512 | GEO

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