Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic.
Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic.
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DOI：
10.18632/aging.204616
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发表时间：
2023-03-28
期刊：
影响因子：
5.2
通讯作者：
Macip, Salvador
中科院分区：
文献类型：
--
作者：
Al-Mansour, Fares;Alraddadi, Abdullah;He, Buwei;Saleh, Anes;Poblocka, Marta;Alzahrani, Wael;Cowley, Shaun;Macip, Salvador
衰老细胞的积累在衰老和许多与年龄相关的病理中观察到的表型变化中起着重要作用。因此，旨在预防这些影响的策略，统称为老年治疗，具有很强的临床潜力。抗衰老药物是一种旨在从组织中特异性消除衰老细胞的衰老疗法。已经发现了几种具有抗衰老特性的小分子化合物，但它们的特异性和作用范围是可变的。正因为如此，潜在的新型抗衰老药物正在积极研究中。鉴于hdac和PI3K通路参与衰老，我们假设双重抑制剂CUDC-907可能具有抗衰老作用，CUDC-907是一种已经在临床试验中的抗肿瘤药物。在这里，我们发现CUDC-907确实能够选择性地诱导p53表达导致衰老的细胞凋亡，但在没有p53的情况下发生衰老时则不能。与此一致的是，CUDC-907在不同的应力诱导衰老模型中表现出抗衰老特性。我们的研究结果还表明，CUDC-907的衰老功能依赖于hdac和PI3K的抑制作用，从而导致p53的增加和BH3促生存蛋白的减少。综上所述，我们的研究结果表明，CUDC-907有可能在涉及应激诱导衰老的病理条件下成为临床相关的抗衰老药物。
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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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
9
作者：
通讯作者：
--
DOI：
10.18632/aging.100023
发表时间：
2009-02-13
期刊：
Aging
影响因子：
--
作者：
Dimauro T;David G
通讯作者：
David G
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
7.8
作者：
Gonzalez-Gualda, Estela;Paez-Ribes, Marta;Munoz-Espin, Daniel
通讯作者：
Munoz-Espin, Daniel