Research Paper Volume 12, Issue 9 pp 8221—8240

Identification of SYK inhibitor, R406 as a novel senolytic agent

Hyun-Ji Cho 1, 2, , Eun Jae Yang 3, , Joon Tae Park 4, , Jae-Ryong Kim 5, , Eok-Cheon Kim 5, , Kyong-Jin Jung 5, , Sang Chul Park 1, 6, 7, , Young-Sam Lee 1, 3, ,

  • 1 Well Aging Research Center, DGIST, Daegu 42988, Korea
  • 2 Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 42472, Korea
  • 3 Department of New Biology, DGIST, Daegu 42988, Korea
  • 4 Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea
  • 5 Department of Biochemistry and Molecular Biology, Smart-Aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu 42415, Korea
  • 6 Department of Molecular Medicine, Chonnam National University Medical School, Gwangju 58128, Korea
  • 7 The Future Life and Society Research Center, Chonnam National University, Gwangju 58128, Korea

received: October 29, 2019 ; accepted: March 24, 2020 ; published: May 7, 2020 ;

https://doi.org/10.18632/aging.103135
How to Cite

Copyright © 2020 Cho et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The selective removal of senescent cells by senolytics is suggested as a potential approach to reverse aging and extend lifespan. Using high-throughput screening with replicative senescence of human diploid fibroblasts (HDFs), we identified a novel senolytic drug R406 that showed selective toxicity in senescent cells. Using flow cytometry and caspase expression analysis, we confirmed that R406 caused apoptotic cell death along with morphological changes in senescent cells. Interestingly, R406 altered the cell survival-related molecular processes including the inhibition of phosphorylation of the focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK) in senescent cells. This pattern was not observed in other known senolytic agent ABT263. Correspondingly, apoptotic cell death in senescent cells was induced by simultaneously blocking the FAK and p38 pathways. Taken together, we suggest that R406 acts as a senolytic drug by inducing apoptosis and reducing cell attachment capacity.

Abbreviations

ATCC: American Type Culture Collection; HUVEC: human umbilical vein endothelial cells; DMEM: Dulbecco’s modified Eagle’s medium; FBS: fetal bovine serum.