The methylating agent streptozotocin induces persistent telomere dysfunction in mammalian cells

Abstract

We analyzed chromosomal aberrations involving telomeres in the progeny of mammalian cells exposed to the methylating agent and antineoplastic/diabetogenic drug streptozotocin (STZ), to test whether it induces long-term telomere instability (by chromosome end loss and/or telomere dysfunction). Rat cells (ADIPO-P2 cell line, derived from Sprague-Dawley rat adipose cells) were treated with a single concentration of STZ (2mM). Chromosomal aberrations were analyzed 18h, 10 days, and 15 days after treatment, using PNA-FISH with a pan-telomeric probe [Cy3-(CCCTAA)3] to detect (TTAGGG)n repeats. Cytogenetic analysis revealed a higher frequency of chromosomal aberrations in STZ-exposed cultures vs. untreated cultures at each time point analyzed. The yield of induced aberrations was very similar at each time point. Induction of aberrations not involving telomere dysfunction was only observed 18h and 15 days after treatment, whereas induction of telomere dysfunction-related aberrations by STZ (mainly in the form of telomere FISH signal loss and duplications, most of them chromatid-type aberrations) was observed at each time point. Our results show that STZ induces persistent telomere instability in mammalian cells, cytogenetically manifested as telomere dysfunction-related chromosomal aberrations. Neither telomere length nor telomerase activity is related to the telomere dysfunction.

Telomere Instability Induced by Anticancer Drugs in Mammalian Cells

“…In addition, our experiments with rat cells exposed to STZ showed that this compound also induces long-term telomere instability in the form of incomplete chromosome elements, as previously observed in the short-term in Chinese hamster cells [57]. We found that STZ induces a transient increase in telomere length in ADIPO-P2 cells at 10 days after treatment, a delayed effect not related with telomerase activity, which remained unchanged in both treated and untreated cells [62]. Therefore, the persistence of chromosomal aberrations related to telomere dysfunction in rat cells exposed to STZ seems to be unrelated to telomerase activity or telomere length.…”

“…Finally, we found that also STZ induces persistent telomere dysfunction in rat cells, cytogenetically detected mainly as telomere FISH signal loss and duplications, most of them being chromatid-type aberrations [62]. We observed that STZ induces significantly more signal loss than duplications, telomere loss thus being the most significant effect of STZ on telomere function at the chromosome level in ADIPO-P2 cells.…”

Streptozotocin Impairs Proliferation and Differentiation of Adult Hippocampal Neural Stem Cells in Vitro-Correlation With Alterations in the Expression of Proteins Associated With the Insulin System

“…injections (Reaven and Ho, 1991 ; Wang and Gleichmann, 1998 ; Yuan et al, 2016 ). STZ treatment causes typical aging-associated changes, such as telomere instability (Paviolo et al, 2015 ), mitochondrial dysfunction (Raza and John, 2012 ), genomic instability (Attia et al, 2009 ), metabolic dysfunction (Rodríguez-Mañas et al, 2009 ) and cellular senescence (Oubaha et al, 2016 ). Furthermore, T2DM induced by STZ i.p.…”

Effect of Chemotherapeutic Drugs on Telomere Length and Telomerase Activity

“…Concerning streptozotocin, we found that it also has a variable effect on telomere length in the long-term, since this drug had no significant effect at 18 h and 15 days after treatment, but induced telomere elongation at 10 days after treatment. These effects were not related with telomerase activity, which remained unchanged in both treated and untreated cells from 18 h to 15 days after treatment [36] . Therefore, the persistence of chromosomal aberrations related to telomere dysfunction observed in rat cells exposed to streptozotocin seems to be unrelated to telomerase activity or telomere length.…”

“…The effect of these drugs on telomere length in hamster cells was not determined. More recently, we investigated the long-term effect (i.e., up to 15 days after treatment) of bleomycin, streptonigrin and streptozotocin on telomeres of rat cells (the ADIPO-P2 cell line, derived from dedifferentiated adipose cells from Spragüe-Dawley rats) [34][35][36] . Bleomycin and streptonigrin had a variable effect on telomere length, since they both induced telomere shortening at 18 h, telomere elongation at 10 days, and had no effect on telomere length at 15 days after treatment (Paviolo, unpublished).…”