Senolytics and senostatics as adjuvant tumour therapy

Abstract

Cell senescence is a driver of ageing, frailty, age-associated disease and functional decline. In oncology, tumour cell senescence may contribute to the effect of adjuvant therapies, as it blocks tumour growth. However, this is frequently incomplete, and tumour cells that recover from senescence may gain a more stem-like state with increased proliferative potential. This might be exaggerated by the induction of senescence in the surrounding niche cells. Finally, senescence will spread through bystander effects, possibly overwhelming the capacity of the immune system to ablate senescent cells. This induces a persistent system-wide senescent cell accumulation, which we hypothesize is the cause for the premature frailty, multi-morbidity and increased mortality in cancer survivors. Senolytics, drugs that selectively kill senescent cells, have been developed recently and have been proposed as second-line adjuvant tumour therapy. Similarly, by blocking accelerated senescence following therapy, senolytics might prevent and potentially even revert premature frailty in cancer survivors. Adjuvant senostatic interventions, which suppress senescence-associated bystander signalling, might also have therapeutic potential. This becomes pertinent because treatments that are senostatic in vitro (e.g. dietary restriction mimetics) persistently reduce numbers of senescent cells in vivo, i.e. act as net senolytics in immunocompetent hosts.

Selective Vulnerability of Senescent Glioblastoma Cells to Bcl-XL Inhibition

“…Indeed, significant overlap exists between phenotypic characteristics of malignant and senescent cells. [12][13] However, while malignant cells are defined in part by proliferative behavior, senescent cells, by definition, do not divide. We evaluated single fraction radiation doses in human glioblastoma cell lines and observed sustained loss of culture expansion with 8Gy or higher radiation in the GBM39 cell line (Figure 1).…”

“…p53 is a key regulator of cell cycle arrest in the context of radiation-induced DNA damage and senescence, and is the most commonly mutated gene across human cancers. [28] [29] Although several lines with some of the most robust relative sensitivity to BCL-XL (in radiated vs nonradiated cells) were WT for p53 (e.g., GBM 10,39,76,114), highly significant induction was also observed in p53-mutant cell lines ( GBM 6,12,132,196). Similarly, no clear p53 pattern followed for cells with modest radiation-induced induction BCL-XL inhibitor sensitivity: P53-mutant GBM123 showed only 2.5x induction of A1331852 sensitivity (results were more robust for A1155 and Navitoclax, Figure 3), yet p53-WT GBM 164 showed minimally significant difference between radiated and non-radiated cells for both A133A852 and Navitoclax.…”

“…Consistent with certain overlapping biology between senescence and malignancy, some senolytic drugs have known anti-tumor activity. [12] [14] We investigated whether prior radiation increases sensitivity to senolytic agents. The senolytic drugs tested and their associated senescent cell associated pathways (SCAPs) are detailed in Table 1.…”

Mechanisms and significance of therapy-induced and spontaneous senescence of cancer cells

“…2 Therapy-induced senescence of cancer cells from the perspective of the ambivalent, either positive or negative outcomes of this process for a patient alternative therapeutic solution for oncologic patients. There seems to be, however, a chance to take such an approach seriously when the senescence-inducing therapy could be restricted exclusively to cancerous cells or reasonably combined with specific, e.g., SASP-targeting senolytics [143], alternatively drugs which block the SASP without eliminating senescent cells, referred to as senostatics [144]. Recent years provided multiple information regarding biological effects exerted by the both classes of anti-senescence drugs, that allow to consider them as valuable adjuvants in cancer therapy.…”

The hubris and humility of cancer pharmacology in the post immuno‐oncology era

“…Complementary processes that inhibit cell replication include anoikis, which is anchorage loss‐dependent death; necroptosis, which is a caspase‐independent, inflammatory cell death; ferroptosis, which is an iron‐dependent oxidative cell death; and senescence, which is irreversible cell cycle inhibition coupled with the secretion of cytokines, growth factors and proteases . There is considerable interest in finding therapeutics that disrupt many of these processes and the reader is directed to some useful reviews for further details …”