HTiP: High-Throughput Immunomodulator Phenotypic Screening Platform to Reveal IAP Antagonists as Anti-cancer Immune Enhancers

Mo, Xiulei; Tang, Cong; Niu, Qiankun; Ma, Tingxuan; Du, Yuhong; Fu, Haian

doi:10.1016/j.chembiol.2018.11.011

Cited by 42 publications

(34 citation statements)

References 41 publications

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“…The identification of new drugs and regulatory pathways that promote the activation of endogenous thermogenic adipocytes may result in the development of new therapeutics for the treatment of metabolic diseases, such as diabetes and/or obesity. To test the utility of beige adipocytes for drug discovery, the LOPAC and Emory Enriched Bioactive Library 44 (Fig. 6a) were screened using a lipolysis assay (glycerol release) in a 384-well plate format.…”

Section: And 8)mentioning

confidence: 99%

“…All cell culture and incubations in the 384-well format were done at 37°C and 5% CO 2 . Compounds from the library of pharmacologically active compounds (LOPAC, Sigma) and the Emory Enriched Bioactive Library 44 (3889 in total) were added at a final concentration of 20 μM. The LOPAC library are composed of 1280 biologically active compounds and impacts most signaling pathways and drug classes, including cell signaling, phosphorylation, cell stress, ion channels, G-protein coupled receptors, hormone, and cell cycle regulators.…”

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confidence: 99%

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Human beige adipocytes for drug discovery and cell therapy in metabolic diseases

et al. 2020

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Human beige adipocytes (BAs) have potential utility for the development of therapeutics to treat diabetes and obesity-associated diseases. Although several reports have described the generation of beige adipocytes in vitro, their potential utility in cell therapy and drug discovery has not been reported. Here, we describe the generation of BAs from human adiposederived stem/stromal cells (ADSCs) in serum-free medium with efficiencies >90%. Molecular profiling of beige adipocytes shows them to be similar to primary BAs isolated from human tissue. In vitro, beige adipocytes exhibit uncoupled mitochondrial respiration and cAMP-induced lipolytic activity. Following transplantation, BAs increase whole-body energy expenditure and oxygen consumption, while reducing bodyweight in recipient mice. Finally, we show the therapeutic utility of BAs in a platform for high-throughput drug screening (HTS). These findings demonstrate the potential utility of BAs as a cell therapeutic and as a tool for the identification of drugs to treat metabolic diseases.

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Human beige adipocytes for drug discovery and cell therapy in metabolic diseases

et al. 2020

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“…2D cultures can be co-cultured with different types of exogenously added heterogeneous cells to simulate cell-cell communication in tumors [ 14 – 16 ]. Addition of peripheral blood mononuclear cells (PBMCs) can be used for exploration of immunotherapeutic agents [ 17 ]. Furthermore, such reconstituted cells are typically not from the endogenous intratumoral stroma, and adherent monolayer cancer cells do not replicate 3D morphological structures.…”

Section: Organoid Culture Systems For Modeling the Tumor Immune Micromentioning

confidence: 99%

Organoid Models of Tumor Immunology

Yuki

Cheng

Nakano

et al. 2020

Trends in Immunology

268

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Cellular interactions in the tumor microenvironment (TME) significantly govern cancer progression and drug response. The efficacy of clinical immunotherapies has fostered an exponential interest in the tumor immune microenvironment, which in turn has engendered a pressing need for robust experimental systems modeling patient-specific tumor-immune interactions. Traditional 2D in vitro tumor immunotherapy models have reconstituted immortalized cancer cell lines with immune components, often from peripheral blood. However, newly developed 3D in vitro organoid culture methods now allow the routine culture of primary human tumor biopsies and increasingly incorporate immune components. Here, we present a viewpoint on recent advances, and propose translational applications of tumor organoids for immuno-oncology research, immunotherapy modeling, and precision medicine.

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“…In addition to their effect on the tumor cells, SM-induced loss of cIAP1/2 in immune cells can activate the alternative NF-κB pathway, which promotes B-cell survival and provides a broad co-stimulatory signal to dendritic cells and T cells [79]. These signals can further induce an immune-modulatory activity, resulting in the massive secretion of proinflammatory cytokines against cancer cells [80,81]. However, high-dose SM treatment may have side effects that can lead to systemic toxicity, to cytokine release syndrome, or to blunting of tumor responses to the death ligands.…”

Section: Mechanism Of Action Of Smsmentioning

confidence: 99%

Potency and Selectivity of SMAC/DIABLO Mimetics in Solid Tumor Therapy

Zhao

Wang

Wei

et al. 2020

Cells

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Aiming to promote cancer cell apoptosis is a mainstream strategy of cancer therapy. The second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosis protein (IAP)-binding protein with low pI (DIABLO) protein is an essential and endogenous antagonist of inhibitor of apoptosis proteins (IAPs). SMAC mimetics (SMs) are a series of synthetically chemical compounds. Via database analysis and literature searching, we summarize the potential mechanisms of endogenous SMAC inefficiency, degradation, mutation, releasing blockage, and depression. We review the development of SMs, as well as preclinical and clinical outcomes of SMs in solid tumor treatment, and we analyze their strengths, weaknesses, opportunities, and threats from our point of view. We also highlight several questions in need of further investigation.

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HTiP: High-Throughput Immunomodulator Phenotypic Screening Platform to Reveal IAP Antagonists as Anti-cancer Immune Enhancers

Cited by 42 publications

References 41 publications

Human beige adipocytes for drug discovery and cell therapy in metabolic diseases

Human beige adipocytes for drug discovery and cell therapy in metabolic diseases

Organoid Models of Tumor Immunology

Potency and Selectivity of SMAC/DIABLO Mimetics in Solid Tumor Therapy

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