Galactose-modified duocarmycin prodrugs as senolytics.,Aging Cell

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Galactose-modified duocarmycin prodrugs as senolytics.
Aging Cell ( IF 8.0 ) Pub Date : 2020-03-16 , DOI: 10.1111/acel.13133
Ana Guerrero _{1,

2} , Romain Guiho ₃ , Nicolás Herranz _{1,

2} , Anthony Uren _{1,

2} , Dominic J Withers _{1,

2} , Juan Pedro Martínez-Barbera ₃ , Lutz F Tietze ₄ , Jesús Gil _{1,

2}

Affiliation

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 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, and this has been exploited as a marker for senescence (senescence‐associated β‐galactosidase activity). Consequently, we hypothesized 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 treatment of mice. Moreover, taking advantage of a mouse model of adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD prodrug selectively reduced the number of β‐catenin‐positive preneoplastic senescent cells. In summary, the above results make a case for testing the potential of galactose‐modified duocarmycin prodrugs to treat senescence‐related pathologies.

中文翻译：

半乳糖修饰的多卡霉素前药作为 senolytics。

衰老是一种稳定的生长停滞，会损害受损、衰老或肿瘤前细胞的复制，从而有助于组织稳态。衰老细胞在衰老过程中积累，与癌症、纤维化和许多与年龄相关的病理有关。最近的证据表明，选择性消除衰老细胞可以有效治疗许多与衰老相关的疾病。衰老细胞的一个普遍特征是它们表现出溶酶体 β-半乳糖苷酶活性升高，这已被用作衰老的标志物（衰老相关的 β-半乳糖苷酶活性）。因此，我们假设半乳糖修饰的细胞毒性前药将优先被衰老细胞加工，导致其选择性杀死。在这里，我们发现不同的半乳糖修饰的多卡霉素（GMD）衍生物优先杀死衰老细胞。 GMD 前药以溶酶体 β-半乳糖苷酶 (GLB1) 依赖性方式诱导衰老细胞选择性凋亡。 GMD 前药可以消除培养物中的多种衰老细胞，并且用 GMD 前药治疗可增强对小鼠全身辐射治疗时积累的旁观者衰老细胞的消除。此外，利用小鼠金刚质瘤性颅咽管瘤（ACP）模型，我们发现用 GMD 前药治疗可选择性减少 β-连环蛋白阳性癌前衰老细胞的数量。总之，上述结果为测试半乳糖修饰的多卡霉素前药治疗衰老相关病理的潜力提供了理由。

更新日期：2020-03-16

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