Is it Possible to Safely Tip the Balance in Cancer Treatment Towards Cell Death Rather than Cell Senescence?

Most cancer treatments produce a lot of senescent cells in the course of killing cancerous cells. This is thought to be the primary reason as to why cancer survivors have a reduced life expectancy and greater burden of age-related disease. Senescent cells secrete disruptive, inflammatory signals that harm tissue function when consistently present. Growing numbers of senescent cells in old tissues are an important contribution to degenerative aging.

The straightforward approach to this issue would be to treat cancer patients with senolytic therapies to clear senescent cells after the anti-cancer treatment is complete. Whether or not one can usefully interfere during the anti-cancer treatments is an interesting question, and one that likely lacks a simple answer. Here researchers conduct a preliminary investigation of one potential point of intervention that appears to bias cells towards destruction rather than senescence, but only in some cancer types and treatment types. A great deal of further work would need to take place in order to determine whether this is actually safe in the scenario of cancer therapies.

A number of anti-cancer strategies, which are based on chemotherapy, radiotherapy, and immunotherapy or the use of CDK4/CDK6 inhibitors and epigenetic modulators may promote cellular senescence in cancer and normal cells and tissues as an adverse side effect. Cellular senescence, a state of permanent cell cycle arrest with well characterized biochemical and molecular biomarkers, is considered to be a tumor suppressor mechanism and tissue repair and regeneration modulator. However, in some circumstances, cellular senescence may also stimulate chronic inflammation and tumorigenesis in aged organisms.

DNMT2/TRDMT1 methyltransferase is implicated in the regulation of cellular lifespan and DNA damage response (DDR). It was suggested that DNMT2/TRDMT1 might be considered as a novel target in cancer therapy as the loss of DNMT2/TRDMT1 sensitized cancer cells to PARP inhibitors. In the present study, the responses to senescence-inducing concentrations of doxorubicin and etoposide in different cancer cells with DNMT2/TRDMT1 gene knockout were evaluated, including changes in the cell cycle, apoptosis, autophagy, interleukin levels, genetic stability and DDR.

Diverse responses were revealed that was based on type of cancer cells (breast and cervical cancer, osteosarcoma and glioblastoma cells) and anti-cancer drugs. DNMT2/TRDMT1 gene knockout in drug-treated glioblastoma cells resulted in decreased number of apoptotic and senescent cells, IL-8 levels, and autophagy, and increased number of necrotic cells, DNA damage, and affected DDR compared to drug-treated glioblastoma cells with unmodified levels of DNMT2/TRDMT1. We suggest that DNMT2/TRDMT1 gene knockout in selected experimental settings may potentiate some adverse effects associated with chemotherapy-induced senescence.


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