Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Human Cell Lines, Reagents and Inhibitor Exposure
2.2. Cell Proliferation and WST-1 Proliferation Assay
2.3. Apoptosis Assay
2.4. Cell Cycle Analysis
2.5. May–Grunwald Giemsa Staining
2.6. RNA Extraction and Isolation
2.7. RNA Sequencing and Microarray Analyses
2.8. RNA Sequencing and Microarray Analysis Pipeline
2.9. Platform Comparison
2.10. Statistics, Reproducibility and Bliss Calculation
3. Results
3.1. Both the Isoform-Specific Bivalent- and Pan-BET Inhibitor Affect Proliferation and Metabolic Activity at Low Dosage in DLBCL and BL Cell Lines
3.2. Entospletinib Reduced Cell Viability of the DLBCL Cell Line SU-DHL-4 Selectively
3.3. Simultaneous BET and SYK Inhibition Revealed a Moderate Synergistic Effect Compared to Single Agent Response
3.4. Simultaneous BET and SYK Inhibition Modulates Cell Morphology Moderately
3.5. Simultaneous BET and SYK Inhibition-Induced Cell Cycle Blockade in DLBCL and BL Cell Lines, but Not Apoptosis
3.6. Combined BET and SYK Inhibition Boost the Changes in Gene Expression
3.7. RNAseq Data Validation by Microarray Analyses—Platform Comparison
3.8. Ento+AZD Combination Intensified the Gene Expression Changes Compared to the Single Agents and Induced a Specific Gene Set Modulation
3.9. Gene Ontology Enrichment Analyses Identified DNA Replication as the Biological Process Most Modulated by the Ento+AZD Combined Exposure
3.10. GO Term Clusters Revealed DNA Replication and Cell Cycle as the Most Affected Cell Biological Processes by the Ento+AZD Combination
4. Discussion
4.1. Both BET Inhibitors Efficiently Affected Cell Proliferation in B-Lymphoma Cell Lines
4.2. Simultaneous BET and SYK Inhibition Additionally Affected Cell’s Response
4.3. Simultaneous BET and SYK Inhibition Identified a Combination-Specific Gene Signature in DLBCL Cell Line SU-DHL-4
4.4. Overlapping DEGs between RNAseq and Microarray Platform in DLBCL Cell Line SU-DHL-4
4.5. Comparison of Identified DEGs Affected by Ento+AZD Combinaton with External Gene Lists
4.6. Gene Ontology (GO) Enrichment Analyses Identified Combination-Specific Biological Processes
4.7. Main GO Clusters in SU-DHL-4 after Combined Exposure
5. Conclusions and Future Perspective
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Sender, S.; Sultan, A.W.; Palmer, D.; Koczan, D.; Sekora, A.; Beck, J.; Schuetz, E.; Taher, L.; Brenig, B.; Fuellen, G.; et al. Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach. Cancers 2022, 14, 4691. https://doi.org/10.3390/cancers14194691
Sender S, Sultan AW, Palmer D, Koczan D, Sekora A, Beck J, Schuetz E, Taher L, Brenig B, Fuellen G, et al. Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach. Cancers. 2022; 14(19):4691. https://doi.org/10.3390/cancers14194691
Chicago/Turabian StyleSender, Sina, Ahmad Wael Sultan, Daniel Palmer, Dirk Koczan, Anett Sekora, Julia Beck, Ekkehard Schuetz, Leila Taher, Bertram Brenig, Georg Fuellen, and et al. 2022. "Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach" Cancers 14, no. 19: 4691. https://doi.org/10.3390/cancers14194691