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：

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半乳糖修饰的杜卡霉素前药为senolytics。

衰老是一种稳定的生长停滞，损害受损的，旧的或肿瘤前细胞的复制，从而促进组织体内稳态。衰老细胞在衰老过程中积累，并与癌症，纤维化和许多与年龄有关的病理相关。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。衰老细胞的普遍特征是它们显示出溶酶体β-半乳糖苷酶的活性升高，并且已被开发为衰老的标志物（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处理，从而导致其选择性杀伤。这里，我们表明，不同的半乳糖修饰的杜卡霉素（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的选择性凋亡。GMD前药可以消除培养物中的大量衰老细胞，而GMD前药的处理可以增强对小鼠全身照射治疗后积累的旁观者衰老细胞的清除。此外，我们利用金刚起瘤性颅咽管瘤（ACP）的小鼠模型，证明了GMD前药治疗选择性地减少了β-catenin阳性肿瘤前衰老细胞的数量。总之，以上结果为检验半乳糖修饰的杜卡霉素前药治疗衰老相关病理的可能性提供了依据。