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Pharmaceuticals 2016, 9(2), 23; doi:10.3390/ph9020023

Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts

1
Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF 14 4XN, UK
2
Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9QJ, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Jean Jacques Vanden Eynde
Received: 24 March 2016 / Revised: 21 April 2016 / Accepted: 25 April 2016 / Published: 28 April 2016
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Abstract

Progeroid syndromes show features of accelerated ageing and are used as models for human ageing, of which Werner syndrome (WS) is one of the most widely studied. WS fibroblasts show accelerated senescence that may result from p38 MAP kinase activation since it is prevented by the p38 inhibitor SB203580. Thus, small molecule inhibition of p38-signalling may be a therapeutic strategy for WS. To develop this approach issues such as the in vivo toxicity and kinase selectivity of existing p38 inhibitors need to be addressed, so as to strengthen the evidence that p38 itself plays a critical role in mediating the effect of SB203580, and to find an inhibitor suitable for in vivo use. In this work we used a panel of different p38 inhibitors selected for: (1) having been used successfully in vivo in either animal models or human clinical trials; (2) different modes of binding to p38; and (3) different off-target kinase specificity profiles, in order to critically address the role of p38 in the premature senescence seen in WS cells. Our findings confirmed the involvement of p38 in accelerated cell senescence and identified p38 inhibitors suitable for in vivo use in WS, with BIRB 796 the most effective. View Full-Text
Keywords: BIRB 796; cell ageing; fibroblasts; p38 MAP kinase; premature ageing; progeroid syndromes; SB203580; therapeutics; UR13756; VX-745 BIRB 796; cell ageing; fibroblasts; p38 MAP kinase; premature ageing; progeroid syndromes; SB203580; therapeutics; UR13756; VX-745
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Davis, T.; Brook, A.J.C.; Rokicki, M.J.; Bagley, M.C.; Kipling, D. Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts. Pharmaceuticals 2016, 9, 23.

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