Telomeric impact of conventional chemotherapy

Abstract

The increased level of chromosome instability in cancer cells, leading to aneuploidy and gross chromosomal rearrangements, is not only a driving force for oncogenesis but also can be the Achille's heel of the disease since many chemotherapies (CT) kill cells by inducing a non-tolerable rate of DNA damage. A wealth of published evidence showed that telomere stability can be more affected than the bulk of the genome by several conventional antineoplasic drugs. These results raise the interesting possibility that CT with genotoxic drugs preferentially target telomeres. In agreement with this view, accelerated shortening of telomere length has been described in blood lineage cells following high-dose CT (stem cell transplantation) or non-myeloablative CT. However, almost nothing is known on the consequences of this shortening in terms of telomere stability, senescence and on the development of second cancers or post-treatment aging-like syndromes in cancer survivors (cognitive defect, fertility impairment, etc.). In this article, we propose: (1) telomeres of cancer cells are preferential genomic targets of chemotherapies altering chromosome maintenance; (2) telomere functional parameters can be a surrogate marker of chemotherapy sensitivity and toxicity; (3) the use of anti-telomere molecule could greatly enhance the sensitivity to standards chemotherapies.

Predicting chemotherapeutic drug combinations through gene network profiling

“…1 ). Overall, these findings are consistent with the previous hypothesis 34 that genomic instability at the telomere underlies cytotoxicity of chemotherapeutic drugs towards human cancer cells.…”

SIRT6 interacts with TRF2 and promotes its degradation in response to DNA damage

“…Although DNA damage induced by drugs used in conventional chemotherapy are usually believed to occur throughout genome, a wealth of evidence indicates that telomeres are preferred targets of several genotoxic molecules (62). Here, we investigated the role of the telomere protein TRF2 in the response to camptothecin (CPT), a Topoisomerase I inhibitor that triggers both single- and double-stranded DNA breaks (DSBs).…”

Disease drivers of aging

“…In contrast, highly active antiretroviral therapy (ART) in HIV appears to accelerate telomere attrition. Chemotherapy can work through telomere damage of both cancerous cells and healthy cells …”

“…Chemotherapy can work through telomere damage of both cancerous cells and healthy cells. 18 While cell aging predicts disease, once one has disease, there is undoubtedly a clouded and complex picture, where both disease processes and aspects of treatment can further affect telomere stability and repair, and thus rate of attrition over time.…”