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Combinations of Kinase Inhibitors Protecting Myoblasts against Hypoxia
- Source :
- PLoS ONE, Vol 10, Iss 6, p e0126718 (2015), PLoS ONE
- Publication Year :
- 2015
- Publisher :
- Public Library of Science (PLoS), 2015.
-
Abstract
- Cell-based therapies to treat skeletal muscle disease are limited by the poor survival of donor myoblasts, due in part to acute hypoxic stress. After confirming that the microenvironment of transplanted myoblasts is hypoxic, we screened a kinase inhibitor library in vitro and identified five kinase inhibitors that protected myoblasts from cell death or growth arrest in hypoxic conditions. A systematic, combinatorial study of these compounds further improved myoblast viability, showing both synergistic and additive effects. Pathway and target analysis revealed CDK5, CDK2, CDC2, WEE1, and GSK3β as the main target kinases. In particular, CDK5 was the center of the target kinase network. Using our recently developed statistical method based on elastic net regression we computationally validated the key role of CDK5 in cell protection against hypoxia. This method provided a list of potential kinase targets with a quantitative measure of their optimal amount of relative inhibition. A modified version of the method was also able to predict the effect of combinations using single-drug response data. This work is the first step towards a broadly applicable system-level strategy for the pharmacology of hypoxic damage.
- Subjects :
- Cell cycle checkpoint
Myoblasts, Skeletal
Cell
lcsh:Medicine
Mice, Transgenic
Mice, SCID
Biology
Mice
Mice, Inbred NOD
medicine
Animals
Myocyte
lcsh:Science
Protein Kinase Inhibitors
Cells, Cultured
Cyclin-dependent kinase 1
Multidisciplinary
Cell Death
Kinase
Cyclin-dependent kinase 5
Cyclin-dependent kinase 2
lcsh:R
Cell Cycle Checkpoints
Cell Hypoxia
3. Good health
Cell biology
Wee1
medicine.anatomical_structure
Biochemistry
biology.protein
lcsh:Q
Protein Kinases
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 10
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....815cd9491ce7cdf165a4b87299049059