Characterization of HDAC/PI3K Inhibitor CUDC-907 as Novel Senolytic | Aging-US

Описание: Aging-US published this research paper on March 28, 2023 in Volume 15, Issue 7, entitled, "Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic" by researchers from the Mechanisms of Cancer and Aging Laboratory, University of Leicester, Leicester LE1 7RH, United Kingdom; Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, United Kingdom; Clinical Laboratory Sciences Department, College of Applied Medical Sciences, Najran University, Najran 11001, Kingdom of Saudi Arabia; The Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester LE1 7RH, United Kingdom; FoodLab, Faculty of Health Sciences, Universitat Oberta de Catalunya, Barcelona 08018, Spain.
‪@UniversityLeicester‬
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DOI - https://doi.org/10.18632/aging.204616

Corresponding author - Salvador Macip - [email protected]

Abstract

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.

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Keywords - aging, senescence, senolytics, HDAC, PI3K, CUDC-907

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Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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