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Characterization of the HDAC_PI3K inhibitor CUDC-907 as a novel senolytic.pdf (1.27 MB)

Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic

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posted on 2023-05-25, 08:57 authored by F Al-Mansour, A Alraddadi, B He, A Saleh, M Poblocka, W Alzahrani, S Cowley, S Macip

The accumulation of senescent cells has an important role in the phenotypical changes observed in ageing and in many age-related pathologies. Thus, the strategies designed to prevent these effects, collectively known as senotherapies, have a strong clinical potential. Senolytics are a type of senotherapy aimed at specifically eliminating senescent cells from tissues. Several small molecule compounds with senolytic properties have already been identified, but their specificity and range of action are variable. Because of this, potential novel senolytics are being actively investigated. Given the involvement of HDACs and the PI3K pathway in senescence, we hypothesized that the dual inhibitor CUDC-907, a drug already in clinical trials for its antineoplastic effects, could have senolytic effects. Here, we show that CUDC-907 was indeed able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53. Consistent with this, CUDC-907 showed senolytic properties in different models of stress-induced senescence. Our results also indicate that the senolytic functions of CUDC-907 depend on the inhibitory effects of both HDACs and PI3K, which leads to an increase in p53 and a reduction in BH3 pro-survival proteins. Taken together, our results show that CUDC-907 has the potential to be a clinically relevant senolytic in pathological conditions in which stress-induced senescence is involved.

Funding

Understanding the unique properties of the Sin3A histone deacetylase complex in transcription and cell viability

Medical Research Council

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History

Author affiliation

Department of Molecular and Cell Biology, University of Leicester

Version

  • VoR (Version of Record)

Published in

Aging

Volume

15

Issue

7

Pagination

2373 - 2394

Publisher

Impact Journals, LLC

issn

1945-4589

eissn

1945-4589

Copyright date

2023

Available date

2023-05-25

Spatial coverage

United States

Language

eng

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