Abstract
Simple SummaryCellular senescence may contribute to aging and age-related diseases, and the elimination of senescent cells is considered a promising anti-aging strategy. Drug-induced senescence in cancer cells during chemotherapy may also promote a number of adverse effects. Thus, in the present study, the usefulness of three quercetin derivatives as senolytic agents was studied upon stimulation of senescence program in breast cancer cells. We have shown that quercetin derivative with blocked hydroxy groups (QD3) sensitized etoposide-induced senescent breast cancer cells to apoptotic cell death that was accompanied by a decrease in proinflammatory and HSP70-based responses. We suggest that these prosenescent and senolytic activities can be combined to design a novel anti-cancer strategy, at least, against breast cancer cells.Drug-induced senescence program may be activated both in normal and cancer cells as a consequence of chemotherapeutic treatment, leading to some adverse side effects such as senescence-associated secretory phenotype (SASP), secondary senescence, and cancer promotion. Targeted elimination of senescent cells can be achieved by drugs with senolytic activity (senolytics), for example, the plant-derived natural compound quercetin, especially when co-treated with kinase inhibitor dasatinib. In the present study, three quercetin derivatives were synthesized and tested for improved senolytic action against etoposide-induced senescent human normal mammary epithelial cells and triple-negative breast cancer cells in vitro. Transformation of catechol moiety into diphenylmethylene ketal and addition of three acetyl groups to the quercetin molecule (QD3 derivative) promoted the clearance of senescent cancer cells as judged by increased apoptosis compared to etoposide-treated cells. A QD3-mediated senolytic effect was accompanied by decreased SA-beta galactosidase activity and the levels of p27, IL-1β, IL-8, and HSP70 in cancer cells. Similar effects were not observed in senescent normal cells. In conclusion, a novel senolytic agent QD3 was described as acting against etoposide-induced senescent breast cancer cells in vitro. Thus, a new one-two punch anti-cancer strategy based on combined action of a pro-senescence anti-cancer drug and a senolytic agent is proposed.
Highlights
Cellular senescence is a heterogenous and complex stress response that can be triggered by endogenous factors and exogenous stimuli [1,2]
We have documented for the first time that QD3, when used at a relatively low concentration of 1 μM, possessed senolytic activity in etoposide-induced senescent breast cancer cells that was accompanied by decreased pools of p27, IL-1β, IL-8, and HSP70 (Figure 4)
As etoposide promoted less pronounced senescence program in normal corresponding mammary epithelial cells compared to breast cancer cells, more experimental approaches are needed to document senolytic action of QD3 in other normal cells and propose its therapeutic applications
Summary
Cellular senescence is a heterogenous and complex stress response that can be triggered by endogenous factors and exogenous stimuli [1,2]. Senescent cells are characterized by permanent cell cycle arrest, proinflammatory secretory phenotype, and altered metabolic traits [3,4]. A number of compounds with senolytic activity (so called senolytics with the ability to preferentially kill senescent cells) have been reported, namely Bcl-2 family inhibitors, HSP90 inhibitors, p53 pathway targeting compounds, natural products and their analogs, cardiac glycosides, and galactose modified prodrugs [1,2,8,9]. A dietary flavonoid, was first documented to exert senolytic activity against senescent human endothelial cells and mouse bone marrow-derived mesenchymal stem cells (BM-MSCs) [10]
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