Three-Dimensional In Vitro Cell Culture Models for Efficient Drug Discovery: Progress So Far and Future Prospects

Badr-Eldin, Shaimaa M.; Aldawsari, Hibah M; Deb, Pran Kishore; Venugopala, Katharigatta N.

doi:10.3390/ph15080926

Cited by 40 publications

(29 citation statements)

References 212 publications

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“…In addition, we relied on the drug sensitivity data and gene essentiality data on cancer cell lines, which may not capture the mechanisms of action of drugs in the tumor microenvironment. Drug screening based on emerging in-vitro models, such as organoids and 3D cell culture 49,50 , may further rationalize drug discovery and drug repositioning 51,52 .…”

Section: Discussionmentioning

confidence: 99%

A gene essentiality signature enables predicting the mechanism of action of drugs

Wang

Bao

Zheng

et al. 2022

Preprint

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BackgroundCancer drugs often kill cells independent of their putative targets, suggesting the limitation of existing drug target information. The lack of understanding of a drug’s mechanism of action may prevent biomarker identification and ultimately lead to attrition in clinical trials. Current experimental strategies, such as binding affinity assays provide limited coverage at the proteome scale. In this study, we explored whether the integration of loss-of-function genetic and drug sensitivity screening data could define a novel signature to better understand the mechanisms of action of drugs.MethodsLoss-of-function genetic screening data was collected from the DepMap database, while drug sensitivity data were collected from three extensive screening studies, namely CTRP (n = 545), GDSC (n = 198), and PRISM (n = 1448). An L1 penalized regression model using the gene essentiality features was constructed for each drug to predict its sensitivity on multiple cell lines. The optimized model coefficients were then considered as the gene essentiality signature of the drug. We compared the gene essentiality signature with structure-based fingerprints and the gene expression signature of cancer drugs in predictions of their known targets. Finally, we applied the gene essentiality signature to predict the novel targets for a panel of noncancer drugs with potential anticancer efficacy.ResultsWe showed that the gene essentiality signature can predict drug targets and their downstream signaling pathways. Both supervised and unsupervised prediction accuracies were higher than those using chemical fingerprints and gene expression signatures. Pathway analyses of these gene essentiality signatures confirmed key mechanisms previously reported, including the EGFR signaling network for lapatinib, and DNA mismatch repair drugs. Finally, we showed that the gene essentiality signature of noncancer drugs can discover novel targets.ConclusionsIntegrating drug sensitivity data and loss-of-function genetic data enables the construction of gene essentiality signatures that help discover drug targets and their downstream signaling pathways. We found novel targets for noncancer drugs that explain their anticancer efficacy, paving the way for the rational design of drug repurposing.

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Section: Discussionmentioning

confidence: 99%

A gene essentiality signature enables predicting the mechanism of action of drugs

Wang

Bao

Zheng

et al. 2022

Preprint

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“…In vitro cell culture, especially mammalian cell culture requires a culture dish or flask to provide nutrients for cell growth in a proper gas atmosphere, and cell concentrations need to be controlled such that the cultures do not exceed growth limits and are not affected by apoptotic cells ( Eibl et al, 2018 ; Jensen and Teng, 2020 ; Badr-Eldin et al, 2022 ). In droplet microfluidics chips, cell culture is divided into droplet compartments, and culture medium and growth factors are added to the continuous phase to provide the nutrients needed for cell growth.…”

Section: Single-cell Analysis Technique Based On Droplet Microfluidicsmentioning

confidence: 99%

Droplets microfluidics platform—A tool for single cell research

Cheng

et al. 2023

Front. Bioeng. Biotechnol.

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Cells are the most basic structural and functional units of living organisms. Studies of cell growth, differentiation, apoptosis, and cell-cell interactions can help scientists understand the mysteries of living systems. However, there is considerable heterogeneity among cells. Great differences between individuals can be found even within the same cell cluster. Cell heterogeneity can only be clearly expressed and distinguished at the level of single cells. The development of droplet microfluidics technology opens up a new chapter for single-cell analysis. Microfluidic chips can produce many nanoscale monodisperse droplets, which can be used as small isolated micro-laboratories for various high-throughput, precise single-cell analyses. Moreover, gel droplets with good biocompatibility can be used in single-cell cultures and coupled with biomolecules for various downstream analyses of cellular metabolites. The droplets are also maneuverable; through physical and chemical forces, droplets can be divided, fused, and sorted to realize single-cell screening and other related studies. This review describes the channel design, droplet generation, and control technology of droplet microfluidics and gives a detailed overview of the application of droplet microfluidics in single-cell culture, single-cell screening, single-cell detection, and other aspects. Moreover, we provide a recent review of the application of droplet microfluidics in tumor single-cell immunoassays, describe in detail the advantages of microfluidics in tumor research, and predict the development of droplet microfluidics at the single-cell level.

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“…Single cells in suspension clump together to create a loosely bound cluster of cell aggregates in spheroids. Further, the formation of extracellular matrix with cell surface compacts the cell aggregates to form sphere-like structures [ 106 ]. Spheroids are formed during the proliferative phase and provide the distinct advantage of being able to control the size of spheroids and simulate organ-like micro-architecture and morphology [ 107 ].…”

Section: 3d Scaffold-free Systemmentioning

confidence: 99%

New Frontiers in Three-Dimensional Culture Platforms to Improve Diabetes Research

et al. 2023

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Diabetes mellitus is associated with defects in islet β-cell functioning and consequent hyperglycemia resulting in multi-organ damage. Physiologically relevant models that mimic human diabetic progression are urgently needed to identify new drug targets. Three-dimensional (3D) cell-culture systems are gaining a considerable interest in diabetic disease modelling and are being utilized as platforms for diabetic drug discovery and pancreatic tissue engineering. Three-dimensional models offer a marked advantage in obtaining physiologically relevant information and improve drug selectivity over conventional 2D (two-dimensional) cultures and rodent models. Indeed, recent evidence persuasively supports the adoption of appropriate 3D cell technology in β-cell cultivation. This review article provides a considerably updated view of the benefits of employing 3D models in the experimental workflow compared to conventional animal and 2D models. We compile the latest innovations in this field and discuss the various strategies used to generate 3D culture models in diabetic research. We also critically review the advantages and the limitations of each 3D technology, with particular attention to the maintenance of β-cell morphology, functionality, and intercellular crosstalk. Furthermore, we emphasize the scope of improvement needed in the 3D culture systems employed in diabetes research and the promises they hold as excellent research platforms in managing diabetes.

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Three-Dimensional In Vitro Cell Culture Models for Efficient Drug Discovery: Progress So Far and Future Prospects

Cited by 40 publications

References 212 publications

A gene essentiality signature enables predicting the mechanism of action of drugs

A gene essentiality signature enables predicting the mechanism of action of drugs

Droplets microfluidics platform—A tool for single cell research

New Frontiers in Three-Dimensional Culture Platforms to Improve Diabetes Research

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