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Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic
Fares Al-Mansour 1 2 3, Abdullah Alraddadi 1 2, Buwei He 1 4, Anes Saleh 1 2, Marta Poblocka 1 2, Wael Alzahrani 1 2, Shaun Cowley 2, Salvador Macip 1 2 4 5
Abstract:
...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.
PMID: 36988504
Free Full-Text: https://www.aging-us.com/article/204616/text
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