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Emerging evidence has shown that the therapy-induced senescent growth arrest in cancer cells is of durable nature whereby a subset of cells can reinstate proliferative capacity. Promising new drugs named senolytics selectively target senescent cells and commit them into apoptosis. Accordingly, senolytics have been proposed as adjuvant cancer treatment to cull senescent tumor cells, and thus, screening for agents that exhibit senolytic properties is highly warranted. Our study aimed to investigate three agents, sorafenib, rapamycin, and venetoclax for their senolytic potential in doxorubicin-induced senescence in HCT116 cells. HCT116 cells were treated with one of the three agents, sorafenib (5 µM), rapamycin (100 nM), or venetoclax (10 µM), in the absence or presence of doxorubicin (1 µM). Senescence was evaluated using microscopy-based and flow cytometry-based Senescence-associated-β-galactosidase staining (SA-β-gal), while apoptosis was assessed using annexin V-FITC/PI, and Muse caspase-3/-7 activity assays. We screened for potential genes through which the three drugs exerted senolytic-like action using the Human Cancer Pathway Finder PCR array. The three agents reduced doxorubicin-induced senescent cell subpopulations and significantly enhanced the apoptotic effect of doxorubicin compared with those treated only with doxorubicin. The senescence genes IGFBP5 and BMI1 and the apoptosis genes CASP7 and CASP9 emerged as candidate genes through which the three drugs exhibited senolytic-like properties. These results suggest that the attenuation of doxorubicin-induced senescence might have shifted HCT116 cells to apoptosis by exposure to the tested pharmacological agents. Our work argues for the use of senolytics to reduce senescence-mediated resistance in tumor cells and to enhance chemotherapy efficacy. [ABSTRACT FROM AUTHOR]

• La sénescence cellulaire est devenue une nouvelle cible thérapeutique pour les maladies dégénératives liées à l'âge. • L'élimination des cellules sénescentes protège contre la dégradation du cartilage dans des modèles non cliniques d'arthrose. • Plusieurs molécules sénolytiques, qui ciblent les cellules sénescentes, sont en cours d'évaluation dans l'arthrose. • Les sénothérapies cellulaires, basées sur les cellules souches mésenchymateuses ou les vésicules extracellulaires qu'elles secrètent, ouvrent des perspectives pour le traitement de l'arthrose. La sénescence cellulaire est maintenant reconnue comme un mécanisme fondamental du vieillissement et l'élimination des cellules sénescentes est devenue une nouvelle cible thérapeutique pour les maladies dégénératives liées à l'âge, notamment dans l'arthrose. De nouvelles stratégies thérapeutiques qui visent à éliminer les cellules sénescentes ou sénothérapies se sont développées ces dernières années. Un certain nombre de cibles et de molécules thérapeutiques ont été identifiées et sont en cours d'évaluation en phases précliniques ou cliniques. Cette revue a pour objectif de faire le point sur l'avancée des traitements médicamenteux, cellulaires et acellulaires qui pourraient contribuer à retarder ou limiter la progression de l'arthrose. Cellular senescence has emerged as a fundamental mechanism of aging and neutralization of senescent cells has attracted much attention as a new therapeutic target for age-related diseases, including osteoarthritis. Novel therapeutic strategies that aim at eliminating senescent cells, called senotherapies, have been launched during the past few years. A number of therapeutic targets and drugs have been identified and are being evaluated in pre-clinical and clinical phases. Here, we review the growing field of senotherapies, including senolytics, cellular and acellular therapies that could contribute to delay or limit osteoarthritis progression. [ABSTRACT FROM AUTHOR]

Tumor cells undergo senescence in response to both conventional and targeted cancer therapies. The induction of senescence in response to cancer therapy can contribute to unfavorable patient outcomes, potentially including disease relapse. This possibiliy is supported by our findings that tumor cells induced into senescence by doxorubicin or etoposide can give rise to viable tumors in vivo. We further demonstrate sensitivity of these senescent tumor cells to the senolytic ABT‐263 (navitoclax), therefore providing a "two‐hit" approach to eliminate senescent tumor cells that persist after exposure to chemotherapy or radiation. The sequential combination of therapy‐induced senescence and ABT‐263 could shift the response to therapy toward apoptosis by interfering with the interaction between BCL‐XL and BAX. The administration of ABT‐263 after either etoposide or doxorubicin also resulted in marked, prolonged tumor suppression in tumor‐bearing animals. These findings support the premise that senolytic therapy following conventional cancer therapy may improve therapeutic outcomes and delay disease recurrence. [ABSTRACT FROM AUTHOR]

Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy. Using either genetic approaches that clear p16INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis suppresses pathological angiogenesis. Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease. [Display omitted] • Senescent cells accumulate during diabetic retinopathy • Pathological vasculature engages p16INK4A and BCL-xL • Clearance of p16INK4A-expressing cells suppresses pathological angiogenesis • BCL-xL inhibitor UBX1967 eliminates senescent cells and suppresses neovascularization Pathological angiogenesis is a cardinal feature of retinopathies and cancer. Crespo-Garcia, Tsuruda, Dejda et al. demonstrate that diseased blood vessels can be discriminated by their propensity to engage pathways of cellular senescence. They show that targeting senescence effector/anti-apoptotic protein BCL-xL suppresses pathological angiogenesis, providing a target for elimination of deregulated neovascularization. [ABSTRACT FROM AUTHOR]