Abstract
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.
Highlights
Cellular senescence is a stress response that prevents the replication of old, damaged or transformed cells (Herranz & Gil, 2018)
Given the increasing list of senescence-associated diseases and the benefits of senolytic treatment, we propose that galactose-modified duocarmycin (GMD) derivatives and, more generally, galactose-modified prodrugs are a new class of senolytic compounds and they should be tested to assess their therapeutic potential
We add galactose-modified duocarmycin (GMD) prodrugs as a new class of senolytic agents. These GMD prodrugs are converted to their corresponding duocarmycin drugs in a manner dependent on processing by β-galactosidase
Summary
Cellular senescence is a stress response that prevents the replication of old, damaged or transformed cells (Herranz & Gil, 2018). To understand the extent to which GMD prodrugs behave as senolytics, we assessed the effect that prodrug A has on several types of senescent cells To this end, we took advantage of IMR90 cells and induced senescence by etoposide or doxorubicin treatment, irradiation, or serial passage (Figure S4a–d). We took advantage of two previously described GMD prodrugs, JHB76B and JHB35B (Tietze et al, 2009, 2010) Both drugs were effective in selectively eliminating senescent cells (Figure 3f and Figure S5), suggesting that the generation of galactose-modified prodrugs might be a general route to design senolytic compounds. Data represent mean ± SD; n represents number of mice; ns, not significant; *p < .05; **p < .01
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