Cellular senescence promotes adverse effects of chemotherapy and cancer relapse
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Abstract
Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments. Significance: Many genotoxic chemotherapies have debilitating side effects and also induce cellular senescence in normal tissues. The senescent cells remain chronically present where they can promote local and systemic inflammation that causes or exacerbates many side effects of the chemotherapy. Cancer Discov; 7(2); 165–76. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 115
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Through SASP, senescent cells contribute to cancer development, metastasis, treatment failure and increased recurrence risk.
“In addition, through SASP, senescent cells contribute to cancer development162,163 and metastasis164, treatment failure and increased risk of recurrence165.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [165]
The Results section (“Cancer spread and relapse”; page unavailable) reports that removing therapy-induced senescent host cells prevented or delayed relapse in a mouse breast-cancer model. The Discussion links these cells to inflammatory SASP factors and to treatment-limiting toxicity. The paper does not establish that SASP itself causes treatment failure or increased recurrence risk across cancers; the relapse evidence is limited to the mouse model. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe SASP can explain chemotherapy side effects, such as bone marrow suppression, cardiac dysfunction, blood clotting, or cancer relapse.
“The SASP can also explain chemotherapy side effects, such as bone marrow suppression, cardiac dysfunction, blood clotting, or cancer relapse (Demaria et al. 2017; Wiley et al. 2019).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Demaria et al. 2017
The Discussion (page unavailable) links chemotherapy-induced senescent cells and their inflammatory SASP factors to bone marrow suppression, cardiac dysfunction, and cancer relapse in mice. It does not identify blood clotting as an effect, and it does not establish the SASP itself as the cause of every listed outcome. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLoss of senescent cardiomyocytes does not adversely alter cardiac function in aged mice.
“Our study, in accordance with others (Baker et al, 2016; Roos et al, 2016; Demaria et al, 2017), shows that the loss of senescent cardiomyocytes does not adversely alter cardiac function in aged mice.”
From Length-independent telomere damage drives post-mitotic cardiomyocyte senescence (2019) · cites this paper as Demaria et al, 2017
In Results (“Inflammation, bone marrow recovery and heart function”; page unavailable), eliminating senescent cells after doxorubicin treatment almost completely prevented declines in cardiac function. But the paper says those cardiac senescent cells were primarily endothelial cells and fibroblast-like cells, not cardiomyocytes. It therefore does not establish that loss of senescent cardiomyocytes is harmless in aged mice. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCellular senescence encompasses heterogeneous cellular states triggered by prolonged cell stress resulting in irreversible arrest of proliferation and permanent changes to cell function in vivo.
“Cellular senescence, a central hallmark of aging,13,14 encompasses heterogeneous cellular states triggered by prolonged cell stress resulting in the irreversible arrest of proliferation and permanent changes to cell function in vivo.15,16,17,18,19”
From Uncovering the signatures of aging and senescence in the human dorsolateral prefrontal cortex (2026) · cites this paper as [18]
The Introduction describes senescence as a stress response involving irreversible loss of proliferative capacity and changes in gene expression. The Discussion reports persistent senescent cells with altered secretion-related activity in vivo, but does not establish that the triggering stress must be prolonged or that all changes to cell function are permanent. It also does not explicitly characterize senescence as heterogeneous cellular states. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThese detrimental effects were neutralized via genetic or pharmacological clearance of senescent cells.
“Moreover, these detrimental effects were neutralized via genetic or pharmacological clearance of senescent cells 27 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
The Results (Inflammation, bone marrow recovery and heart function; Cancer spread and relapse) describe clearing senescent cells with the p16-3MR/ganciclovir system and with the senolytic ABT-263. The Abstract and Discussion report that clearance reduced several chemotherapy-related harms, but the paper does not say all detrimental effects were neutralized; some inflammatory factors remained, and tumor recurrence was delayed rather than eliminated. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Senescent cells might contribute to the reduced tolerance of older individuals to anticancer therapies.
“Interestingly, high expression of p16 INK4a in circulating Tcells before treatment, presumably a surrogate biomarker of system-wide senescent cell burden, correlates with severe chemotherapy- induced fatigue in patients with breast cancer, suggesting that senescent cells might contribute to the reduced tolerance of older individuals to anticancer therapies 27 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
The Introduction says senescent cells accumulate with age, and the Results (‘Chemotherapy-induced fatigue’; page unavailable) link higher pretreatment T-cell p16INK4a to severe fatigue in women receiving breast-cancer chemotherapy. This supports the suggested role of senescent cells in treatment toxicity, but the paper does not establish that they explain reduced therapy tolerance specifically in older individuals. (LLM, conf=0.82)
Experimental — accuracy not yet measuredStudies in mouse models have demonstrated that TIS promotes cardiac dysfunction, inflammation, bone loss, muscle weakness, renal and hepatic failure, haematopoietic insufficiency, and overall frailty.
“Studies in mouse models have demonstrated that TIS promotes cardiac dysfunction, inflammation, bone loss, muscle weakness, renal and hepatic failure, haematopoietic insufficiency, and overall frailty 27,111,202 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
The Discussion reports that therapy-induced senescent cells contributed to inflammation, cardiac dysfunction and bone marrow suppression in mice; the paper also reports reduced physical activity and strength. It does not establish bone loss or renal or hepatic failure, and its Results describe the observed myelosuppression as mild and transient rather than broad haematopoietic insufficiency. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn patients with cancer, older age (>65 years) is associated with reduced tolerance to anticancer treatment and a greater risk of developing serious AEs.
“In patients with cancer, older age (>65 years) is associated with reduced tolerance to anticancer treatment 27 and a greater risk of developing serious AEs 192 , as well as genetic alterations that might lead to reduced sensitivity to treatment; together these features constitute major hurdles for the successful administration of antineoplastic therapies at efficient doses.”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
The Results section (‘Chemotherapy-induced fatigue’; page unavailable) reports severe chemotherapy-related fatigue in women with breast cancer, but links its risk to a pre-treatment senescence marker, not to age over 65. The analysis was age-adjusted and says the marker predicted toxicity independently of chronological age. The cited paper therefore supports the occurrence of serious treatment-related adverse effects, but not the attributed age-specific increase in risk. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDetrimental effects associated with the chronic presence of senescent cells include increases in local and systemic inflammation and cancer reoccurrence.
“These include increases in local and systemic inflammation and cancer reoccurrence (Demaria et al. 2017).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Demaria et al. 2017
In some cases, triggers cause fibroblasts to enter a non-proliferative state termed senescence, which is distinct from the phenotype of an aged fibroblast.
“In some cases, these triggers cause fibroblasts to enter a non-proliferative state termed ‘senescence’71, which is distinct from the phenotype of an aged fibroblast.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [71]
DOX-induced systemic senescence promotes metastasis in an orthotopic mouse model of breast cancer.
“For example, DOX-induced systemic senescence was found to promote metastasis in an orthotopic mouse model of breast cancer.”
From Drug repurposing for cancer therapy (2024) · cites this paper as [232]
p16INK4a expression is considered a common and robust, albeit not necessarily specific, marker of senescence, and its promoter activity and transcriptional activation are extensively exploited as reporters of senescent cells in vivo.
“p16 INK4a expression is considered a common and robust, albeit not necessarily specific, marker of senescence, and its promoter activity and transcriptional activation are extensively exploited as reporters of senescent cells invivo 20,23,27,28 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
Alkylating agents, topoisomerase inhibitors, γ-irradiation, microtubule inhibitors and, to a lesser extent, vinca alkaloids have all been identified as senescence inducers in preclinical models.
“Alkylating agents 27,95,96 (for example, cisplatin, cyclophosphamide and temozolomide), topoisomerase inhibitors 27,65,91,95 (such as doxorubicin, etoposide and camptothecin) and γ- irradiation 78 , but also microtubule inhibitors 27,97,98 (for example, paclitaxel) and, to a lesser extent, vinca alkaloids 78 (for example, vincristine), have all been identified as senescence inducers in preclinical”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
In tumour-free mice, exposure to the topoisomerase II inhibitor doxorubicin leads to systemically elevated SASP and functional impairment reminiscent of accelerated ageing, which is only explained in part by direct organ toxicity of this chemotherapeutic agent.
“In tumour- free mice, exposure to the topoisomerase II inhibitor doxorubicin leads to systemically elevated SASP and functional impairment reminiscent of accelerated ageing, which is only explained in part by direct organ toxicity of this chemotherapeutic agent 27 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
Doxorubicin-induced systemic senescence contributed to breast cancer metastasis in an orthotopic mouse model.
“Doxorubicin- induced systemic senescence contributed to breast cancer metastasis in an orthotopic mouse model.”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
High expression of p16 INK4a in circulating T cells before treatment correlates with severe chemotherapy-induced fatigue in patients with breast cancer.
“Interestingly, high expression of p16 INK4a in circulating Tcells before treatment, presumably a surrogate biomarker of system-wide senescent cell burden, correlates with severe chemotherapy- induced fatigue in patients with breast cancer, suggesting that senescent cells might contribute to the reduced tolerance of older individuals to anticancer therapies 27 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [27]
SASP mediates harmful effects of senescent cells that accumulate upon chemotherapy treatment, as their chronic presence promotes local and systemic inflammation.
“SASP also mediates the harmful effects of senescent cells which accumulate upon chemotherapy treatment as their chronic presence promotes local and systemic inflammation.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Demaria et al., 2017
Age-related or therapy-induced senescent cells are mainly linked with secretion of inflammatory factors.
“age-related or therapy-induced senescent cells are mainly linked with secretion of inflammatory factors (Baker et al., 2016; Demaria et al., 2017).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Demaria et al., 2017
Elimination of therapy-induced senescent cells can prevent cancer recurrence.
“Elimination of therapy-induced senescent cells can prevent cancer recurrence (Demaria et al., 2017).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Demaria et al., 2017
Senescent cells are implicated in adverse effects of some chemotherapeutic regimens and recurrence of specific neoplasms in mice.
“Moreover, senescent cells have been implicated in the adverse effects of some chemotherapeutic regimens as well as in the recurrence of specific neoplasms, at least in mice [969].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [969]
Therapy-induced senescence plays an important role in determining the outcome of anti-cancer treatment and is responsible for some side effects.
“Therapy-induced senescence plays an important role in determining the outcome of anti-cancer treatment 40, whilst also being responsible for some of its side effects 41.”
From Cardiac glycosides are broad-spectrum senolytics (2019) · cites this paper as [41]
Therapy-induced senescence also contributes to the adverse effects of chemotherapy and radiotherapy.
“whilst also contributing to their side effects 41.”
From Cardiac glycosides are broad-spectrum senolytics (2019) · cites this paper as [41]
Via the SASP, senescent cells contribute to multiple chronic health conditions associated with inflammaging, including atherosclerosis, osteoarthritis, cancer, myeloid skewing in the bone marrow, pulmonary fibrosis, Alzheimer's disease, Parkinson's disease, and insulin resistance.
“Via the SASP, senescent cells contribute to multiple chronic health conditions associated with inflammaging, e.g., atherosclerosis (16), osteoarthritis (17), cancer (18), myeloid skewing in the bone marrow (19), pulmonary fibrosis (20), Alzheimer’s disease and Parkinson’s disease (21–23), and insulin resistance (24).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [18]
Persisting senescent cells have been tied to multiple chronic diseases other than atherosclerosis.
“These persisting senescent cells have been recently tied to multiple chronic diseases other than atherosclerosis, including diabetes mellitus,85 obesity,85 Alzheimer’s disease,86 heart failure,10,87 idiopathic pulmonary fibrosis,88,89 chronic obstructive pulmonary disease,90 chronic kidney disease,91 cancer,92 and osteoarthritis.93”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [92]
Chronic senescence promotes cancer.
“However, chronic senescence promotes cancer.92”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [92]
A chronic SASP contributes to tumorigenesis.
“and paradoxically tumorigenesis (Demaria et al., 2017).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Demaria et al., 2017
Senescence may contribute to reduced patient resilience to cancer therapies.
“However, senescence may contribute to reduced patient resilience to cancer therapies”
From Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies (2020) · cites this paper as [67]
Senotherapeutic drugs could potentially treat a variety of conditions primarily or secondarily mediated by senescent cell accumulation.
“The use of senotherapeutic drugs could potentially be effective in treating a variety of conditions primarily or secondarily mediated by accumulation of senescent cells [6, 33, 67–87].”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [69]
Development of a tumor cell population that escapes from senescence and restarts proliferating may contribute to cancer relapse.
“The development of a tumor cell population that escapes from senescence and restarts proliferating may contribute to cancer relapse [342].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [342]
Senescent cells have been postulated to mediate resistance to therapy and contribute to off-target systemic effects and cancer relapse after standard anticancer regimens.
“Senescent cells have also been postulated to mediate resistance to therapy, while contributing to off-target systemic effects and cancer relapse linked to the treatment with standard anticancer regimens.”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [200]
Whole-body clearance of p16+ cells generated by doxorubicin treatment reduces signs of systemic frailty and limits tumor recurrence.
“In the same model, whole-body clearance of p16 + cells generated by doxorubicin treatment reduces signs of systemic frailty and limits tumor recurrence.200”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [200]
Persistent senescent cells may contribute to detrimental short- and long-term side effects of treatment, as well as to metastases and relapse.
“Indeed, persistent senescent cells may contribute to detrimental short and long-term side effects of treatment, as well as to metastases and relapse (Demaria et al., 2017).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Demaria et al., 2017
Elimination of therapy-induced senescent cells reduced several side-effects of chemotherapy and cancer recurrence in mice.
“the elimination of therapy-induced senescent cells reduced several side-effects of chemotherapy and even cancer recurrence in mice14.”
From A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells (2020) · cites this paper as [14]
Ablation of senescent cells after chemotherapy can prevent or delay cancer relapse and spread to distal tissues.
“Furthermore, ablation of senescent cells after chemotherapy can prevent or delay cancer relapse and spread to distal tissues.59”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [59]
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From discoveries in ageing research to therapeutics for healthy ageing
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Self-citationSenescent cells: an emerging target for diseases of ageing
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Mechanisms and functions of cellular senescence
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Senescence and the SASP: many therapeutic avenues
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“These include increases in local and systemic inflammation and cancer reoccurrence (Demaria et al. 2017).”
BackgroundCellular senescence and senolytics: the path to the clinic
Chaib, S., Tchkonia, T., & Kirkland, J. L. (2022) · Nature Medicine · doi:10.1038/s41591-022-01923-y · Cited by 1,105 · see citing works
Unmasking Transcriptional Heterogeneity in Senescent Cells
Hernandez-Segura, A., de Jong, T. V., Melov, S., Guryev, V., Campisi, J., & Demaria, M. (2017) · Current Biology · doi:10.1016/j.cub.2017.07.033 · Cited by 972 · see citing works
“We induced senescence by various means, including those used in the previous analyses (ionizing radiation, replication, and oxidative stress), as well as doxorubicin, a DNA-damaging chemotherapeutic agent known to cause senescence [30]) (Figures S3A–S3D).”
MethodSelf-citationExploiting senescence for the treatment of cancer
Wang, L., Lankhorst, L., & Bernards, R. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00450-9 · Cited by 867 · see citing works
Unmasking senescence: context-dependent effects of SASP in cancer
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How the ageing microenvironment influences tumour progression
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The senescence-associated secretory phenotype and its physiological and pathological implications
Wang, B., Han, J., Elisseeff, J. H., & Demaria, M. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00727-x · Cited by 948 · see citing works
Self-citationSenescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
Self-citationThe metabolic roots of senescence: mechanisms and opportunities for intervention
Wiley, C. D., & Campisi, J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00483-8 · Cited by 691 · see citing works
Self-citationTargeting senescent cells alleviates obesity-induced metabolic dysfunction
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Self-citationThe dynamic nature of senescence in cancer
Lee, S., & Schmitt, C. A. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0249-2 · Cited by 588 · see citing works
The senescence-associated secretory phenotype and its regulation
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Impaired immune surveillance accelerates accumulation of senescent cells and aging
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Meta-hallmarks of aging and cancer
López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., & Kroemer, G. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2022.11.001 · Cited by 529 · see citing works
Length-independent telomere damage drives post-mitotic cardiomyocyte senescence
Anderson, R., Lagnado, A., Maggiorani, D., Walaszczyk, A., Dookun, E., Chapman, J., Birch, J., Salmonowicz, H., Ogrodnik, M., Jurk, D., et al. (2019) · The EMBO Journal · doi:10.15252/embj.2018100492 · Cited by 532 · see citing works
“Our study, in accordance with others (Baker et al , 2016; Roos et al , 2016; Demaria et al , 2017), shows that the loss of senescent cardiomyocytes does not adversely alter cardiac function in aged mice.”
The quest to slow ageing through drug discovery
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Self-citationAgeing, Cellular Senescence and Neurodegenerative Disease
Kritsilis, M., V. Rizou, S., Koutsoudaki, P. N., Evangelou, K., Gorgoulis, V. G., & Papadopoulos, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102937 · Cited by 448 · see citing works
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Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages
Covarrubias, A. J., Kale, A., Perrone, R., Lopez-Dominguez, J. A., Pisco, A. O., Kasler, H. G., Schmidt, M. S., Heckenbach, I., Kwok, R., Wiley, C. D., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00305-3 · Cited by 420 · see citing works
Self-citationDrug repurposing for cancer therapy
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“232 Pioneering research has shown that senescent cells possess the capability to initiate malignancy in benign cells both in culture and in animal models.”
BackgroundTelomeres and cell senescence—size matters not
Victorelli, S., & Passos, J. F. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.03.027 · Cited by 413 · see citing works
Mitochondria in Cell Senescence: Is Mitophagy the Weakest Link?
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“More importantly, interventions that er the CC BY license (http://creativecommons.org/licenses/by/4.0/). selectively ablate senescent cells by genetic and/or pharmacologic means may improve healthspan and lifespan in mice (Baker et al., 2016; Demaria et al., 2017; Xu et al., 2015).”
BackgroundInfluentialMechanisms and Regulation of Cellular Senescence
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CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought
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SenNet recommendations for detecting senescent cells in different tissues
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“For example, many anticancer therapies have the adverse effect of inducing senescence in healthy, non-cancerous cells, thereby contributing to local and systemic inflammation 5 .”
Self-citationIdentification and characterization of Cardiac Glycosides as senolytic compounds
Triana-Martínez, F., Picallos-Rabina, P., Da Silva-Álvarez, S., Pietrocola, F., Llanos, S., Rodilla, V., Soprano, E., Pedrosa, P., Ferreirós, A., Barradas, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12888-x · Cited by 384 · see citing works
Immunological impact of cell death signaling driven by radiation on the tumor microenvironment
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Cardiac glycosides are broad-spectrum senolytics
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Role of immune cells in the removal of deleterious senescent cells
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Self-citationCD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels
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The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice
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Self-citationA versatile drug delivery system targeting senescent cells
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“We show here that sEVs are responsible for mediating paracrine senescence and speculate that they could be involved in inducing bystander senescence during therapy-induced senescence (Demaria et al., 2017) or aging (Acosta et al.”
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A Senescence-Centric View of Aging: Implications for Longevity and Disease
Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.07.002 · Cited by 267 · see citing works
Self-citationTumor cell escape from therapy-induced senescence as a model of disease recurrence after dormancy.
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Two-Step Senescence-Focused Cancer Therapies
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Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies
Wyld, L., Bellantuono, I., Tchkonia, T., Morgan, J., Turner, O., Foss, F., George, J., Danson, S., & Kirkland, J. L. (2020) · Cancers · doi:10.3390/cancers12082134 · Cited by 235 · see citing works
“In the context of chemotherapy tolerance, there is evidence that some of the adverse effects of chemotherapy are mediated by the therapy-induced senescent cells which have a pro-inflammatory effects (due to SASP) in a doxorubicin or paclitaxel treated mouse model [67].”
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Cellular senescence: the sought or the unwanted?
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A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
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The Cancer SENESCopedia: A delineation of cancer cell senescence
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Senescent Cells: Emerging Targets for Human Aging and Age-Related Diseases
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Algorithmic assessment of cellular senescence in experimental and clinical specimens
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Self-citationReducing Senescent Cell Burden in Aging and Disease
Pignolo, R. J., Passos, J. F., Khosla, S., Tchkonia, T., & Kirkland, J. L. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.03.005 · Cited by 177 · see citing works
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Connecting aging biology and inflammation in the omics era
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Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis
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Fracture Healing in the Setting of Endocrine Diseases, Aging, and Cellular Senescence
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Spatial and Temporal Control of Senescence
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Paracrine roles of cellular senescence in promoting tumourigenesis
Gonzalez-Meljem, J. M., Apps, J. R., Fraser, H. C., & Martinez-Barbera, J. P. (2018) · British Journal of Cancer · doi:10.1038/s41416-018-0066-1 · Cited by 183 · see citing works
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Self-citationOxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis
Wiley, C. D., Sharma, R., Davis, S. S., Lopez-Dominguez, J. A., Mitchell, K. P., Wiley, S., Alimirah, F., Kim, D. E., Payne, T., Rosko, A., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.03.008 · Cited by 173 · see citing works
Self-citationImmunomodulation by anticancer cell cycle inhibitors
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Galactose‐modified duocarmycin prodrugs as senolytics
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Self-citationSenescence and senotherapeutics: a new field in cancer therapy
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A null mutation in <i>SERPINE1</i> protects against biological aging in humans
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The role of cellular senescence and SASP in tumour microenvironment
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Senescence as a therapeutically relevant response to CDK4/6 inhibitors
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Cellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling
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Self-citationSILAC Analysis Reveals Increased Secretion of Hemostasis-Related Factors by Senescent Cells
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Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy
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Oxidation resistance 1 is a novel senolytic target
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Self-citationTargeting Senescent Cells for a Healthier Aging: Challenges and Opportunities
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Senolytics for Cancer Therapy: Is All that Glitters Really Gold?
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Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype
Wiley, C. D., Schaum, N., Alimirah, F., Lopez-Dominguez, J. A., Orjalo, A. V., Scott, G., Desprez, P.-Y., Benz, C., Davalos, A. R., & Campisi, J. (2018) · Scientific Reports · doi:10.1038/s41598-018-20000-4 · Cited by 124 · see citing works
Self-citationCellular senescence, senescence-associated secretory phenotype, and chronic kidney disease
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Pharmacological CDK4/6 inhibition reveals a p53‐dependent senescent state with restricted toxicity
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Self-citationRadiation-induced astrocyte senescence is rescued by Δ133p53
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“In the present study, we first utilized the p16-3MR mouse model, which allows for genetic-based suppression of excess senescent cells, 9,16 to determine the role of cellular senescence and the SASP in mediating vascular”
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- Authors
- Demaria, M., O'Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., Koenig, K., Le, C., Mitin, N., Deal, A. M., Alston, S., Academia, E. C., Kilmarx, S., Valdovinos, A., Wang, B., de Bruin, A., Kennedy, B. K., Melov, S., Zhou, D., Sharpless, N. E., Muss, H., & Campisi, J.
- Affiliations
- University Medical Center Groningen (NL)
- 1Buck Institute for Research on Aging, Novato, California.
- University of Arkansas for Medical Sciences (US)
- Buck Institute for Research on Aging (US)
- 4HealthSpan Diagnostics, Research Triangle Park, North Carolina.
- University of North Carolina at Chapel Hill (US)
- 6Department of Pathobiology, University of Utrecht, Utrecht, the Netherlands.
- Corresponding author
- Demaria, Marco
- Campisi, Judith
- ORCID
- Venue
- Cancer Discovery
- Published
- 2017-02-01
- Volume
- 7
- Issue
- 2
- Pages
- 165-176
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5296251
- OpenAlex
- W2561396377
- Cited by
- 1,338
- References
- 34
- Citations by year
- 2026: 113 · 2025: 153 · 2024: 164 · 2023: 176 · 2022: 198 · 2021: 152 · 2020: 159 · 2019: 105 · 2018: 79 · 2017: 38 · 2013: 1
- FWCI
- 59.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- UNC Libraries
- Funders
- American-Italian Cancer Foundation
- National Institutes of Health (5r01ag024379-15, AG009909, AG017242, AG041122)
- National Institute on Aging (R56AG009909, R01-AG024379, R37AG009909, P01AG041122, P01AG017242)
- National Cancer Institute (R01CA122023, R01CA166347, R01CA203023, R01CA163896, P30CA016086)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- cellular senescence, therapy-induced senescence, chemotherapy toxicity, senescence-associated secretory phenotype, senolytics, senescent cell elimination, inflammation, tumor recurrence, myelosuppression, cardiotoxicity, chemotherapy-induced fatigue, T cells, genotoxic chemotherapy, transgenic mouse model
- MeSH terms
- Animals, Antineoplastic Agents, Breast Neoplasms, Female, Humans, Mice, Transgenic, Neoplasm Recurrence, Local, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Cell Proliferation, Mice
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