Guerrero Ana, Guiho Romain, Herranz Nicolás, Uren Anthony, Withers Dominic J, Martínez-Barbera Juan Pedro, Tietze Lutz F, Gil Jesús
MRC London Institute of Medical Sciences (LMS), London, UK.
Faculty of Medicine, Institute of Clinical Sciences (ICS), Imperial College London, London, UK.
Aging Cell. 2020 Apr;19(4):e13133. doi: 10.1111/acel.13133. Epub 2020 Mar 16.
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.
衰老（过程）是一种稳定的生长停滞状态，它会损害受损细胞、衰老细胞或肿瘤前体细胞的复制，从而有助于维持组织稳态。衰老细胞在衰老过程中会不断积累，并与癌症、纤维化以及许多与年龄相关的病理状况相关联。最近的证据表明，选择性清除衰老细胞可能对治疗许多这类与衰老相关的疾病有效。衰老细胞的一个普遍特征是它们的溶酶体β - 半乳糖苷酶活性升高，这一特性已被用作衰老的标志物（衰老相关β - 半乳糖苷酶活性）。因此，我们推测半乳糖修饰的细胞毒性前药会被衰老细胞优先处理，从而导致对它们的选择性杀伤。在此，我们表明不同的半乳糖修饰的双吖丙啶（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）依赖的方式诱导衰老细胞选择性凋亡。GMD前药能够在培养物中清除广泛类型的衰老细胞，并且用GMD前药进行治疗可增强对在对小鼠进行全身照射治疗后积累的旁观者衰老细胞的清除。此外，利用成釉细胞瘤性颅咽管瘤（ACP）的小鼠模型，我们表明用GMD前药进行治疗可选择性减少β - 连环蛋白阳性的肿瘤前衰老细胞的数量。总之，上述结果为测试半乳糖修饰的双吖丙啶前药治疗与衰老相关病理状况的潜力提供了依据。
