Imperial College London
Professor Dominic Withers

ProfessorDominicWithers

Faculty of Medicine, Institute of Clinical Sciences

Clinical Chair in Diabetes & Endocrinology
 
 
 
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Contact

 

d.withers

 
 
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Location

 

Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Guerrero:2020:10.1111/acel.13133,
author = {Guerrero, A and Guiho, R and Herranz, N and Uren, A and Withers, DJ and Martínez-Barbera, JP and Tietze, LF and Gil, J},
doi = {10.1111/acel.13133},
journal = {Aging Cell},
pages = {1--13},
title = {Galactose-modified duocarmycin prodrugs as senolytics},
url = {http://dx.doi.org/10.1111/acel.13133},
volume = {19},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with diseases, such as cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β-galactosidase this has been exploited as a marker for senescence (senescence-associated β-galactosidase activity). Consequently, we hypothesised that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole body irradiation or doxorubicin treatment of mice. Moreover, taking advantage of a mouse model of human adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD pro-drug result selectively reduced the number of β-catenin-positive preneoplastic senescent cells, what could have therapeutic implications. In summary, the above results show that galactose-modified duocarmycin prodrugs behave as senolytics, suggesting that they could be used to treat a wide range of senescence-related pathologies.</jats:p>
AU  - Guerrero,A
AU  - Guiho,R
AU  - Herranz,N
AU  - Uren,A
AU  - Withers,DJ
AU  - Martínez-Barbera,JP
AU  - Tietze,LF
AU  - Gil,J
DO  - 10.1111/acel.13133
EP  - 13
PY  - 2020///
SN  - 1474-9718
SP  - 1
TI  - Galactose-modified duocarmycin prodrugs as senolytics
T2  - Aging Cell
UR  - http://dx.doi.org/10.1111/acel.13133
UR  - https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13133
UR  - http://hdl.handle.net/10044/1/78063
VL  - 19
ER  -
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