Senolysis and cancer : Therapeutic perspectives

04 - 11 - 2021

Apart from replicativesenescence due to telomere shortening at each mitosis, senescence can be induced prematurely by stresses, such as oxidative, metabolic, genotoxic or oncogenic stresses. In contrast to quiescence – a reversible cell cycle arrest – senescence is characterised by a stable, essentiallyirreversible cell cycle arrest and by morphological changes, metabolic adaptations and a particular secretory profile that ultimately contribute to altering tissue homeostasis. Although it has a tumour-suppressive role throughout life, senescence in its chronic form is paradoxically a harmful process, potentially tumorigenic in the absence of an appropriate immune response.

Depending on the doses used, genotoxic cancer treatments, such as certain chemotherapies or radiotherapies, can induce both the premature senescence of cancer cells (and thus their stabilisation) and their self-destruction by apoptosis (and thus their reduction) – senescence being induced preferentially by low doses. However, senescence induced in this way can lead to resistance to treatment – the senescent state being associated with resistance to apoptosis. Furthermore, some cancer cells manage to overcome this state of senescence and regain their ability to proliferate, resulting in relapses that are often difficult to treat.

However, the induction of senescence as an anti-cancer therapy remains more relevant than ever. t is indeed possible to take advantage of it in order to increase the efficacy of low-dose treatments, while reducing their side effects. Major research efforts are currently being made to develop combined therapiescombining a senomorphic treatment aimed at rendering cancer cells senescent, followed by a senolytic treatment aimed specifically at eliminating them, so as to avoid any relapse or metastasis. Another important aspect of this approach is the concomitant elimination of senescent non-cancerous cells and thus of the deleterious effects of their secretome.

Various strategies can be adopted to eliminate senescent cancer cells. One of them is totarget their resistance to pro-apoptotic signals, and more specifically the anti-apoptotic protein Bcl-2. Inhibitors of this type already exist. Another approach consists more specifically of countering certain metabolic adaptations made by these senescent cells, such as the appearance of a hypercatabolic and glycolytic phenotype after treatment. Competitive inhibitors of glycolysis, such as2-deoxyglucose, have already been used for this purpose. Finally, another possible strategy is to block the deleterious effects of their secretome on the tissue microenvironment. These different approaches offer real prospects for therapeutic intervention.

In parallel, other research is currently aimed at identifying new targets and active compounds, naturalor synthetic, for future senotherapeutic treatments.

Disclaimer : This information is provided for guidance only and is not a substitute for medical advice.

 

References:

Goy E, Abbadie C. Senescence and cancer: double-dealing. Med Sci (Paris) 2018;34(3):223-230.

Fleury H, Malaquin N, Tu V, et al. Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence. Nat Commun 2019;10(1):2556, 1-15

Wyld L, Bellantuono I, Tchkonia T, et al. Senescence and cancer: a review of clinical implications of senescence and senotherapies. Cancers (Basel) 2020;12(8):2134.

Veret D, Brondello JM. Senotherapy: Advances and new clinical perspectives. Med Sci (Paris). 2020;36(12):1135-1142.

Brondello JM, Prieur A, Philippot D, et al. Cellular senescence and the myth of Janus. Med Sci (Paris). 2012;28(3):288-296.

Jordan B. Towards success against senescence ? Med Sci (Paris). 2018;34(10):885-890.

0 Comments

Submit a Comment

Your email address will not be published.