Cited by 235Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsSirtuins and Resveratrol in Medicine

The DOI matches its Crossref record; 123 of the 125 references it cites were found in a registry or an index; none of the 84 sources its claims cite is checked for support yet.

Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

Open access

Wyld, Lynda, Bellantuono, Ilaria, Tchkonia, Tamara, Morgan, Jenna, Turner, Olivia, Foss, Fiona, George, Jayan, Danson, Sarah, Kirkland, James L.·2020·Cancers

DOI 10.3390/cancers12082134PMC PMC7464619

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Abstract

Cellular senescence is a key component of human aging that can be induced by a range of stimuli, including DNA damage, cellular stress, telomere shortening, and the activation of oncogenes. Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease. It may also be a key effector mechanism of many types of anticancer therapies, such as chemotherapy, radiotherapy, and endocrine therapies, both directly and via bioactive molecules released by senescent cells that may stimulate an immune response. However, senescence may contribute to reduced patient resilience to cancer therapies and may provide a pathway for disease recurrence after cancer therapy. A new group of drugs, senotherapies, (drugs which interact with senescent cells to interfere with their pro-aging impacts by either selectively destroying senescent cells (senolytic drugs) or inhibiting their function (senostatic drugs)) are under active investigation to determine whether they can enhance the efficacy of cancer therapies and improve resilience to cancer treatments. Senolytic drugs include quercetin, navitoclax, and fisetin and preclinical and early phase clinical data are emerging of their potential role in cancer treatments, although none are yet in routine use clinically. This article provides a review of these issues.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes how cellular senescence is both tumour-suppressive and potentially tumour-promoting, and how therapy-induced senescence may affect cancer treatment response, recurrence, and patient resilience. It reviews emerging senotherapies—senolytics and senostatics—as potential adjuncts to cancer therapy, noting that none are yet in routine clinical use.

Key findings

Senescence is generally tumour suppressive by preventing proliferation and blocking progression from premalignant to malignant disease, but chronic senescent cells release SASP factors that may promote tumour recurrence, progression, inflammation, and fibrosis.
Therapy-induced senescence is common: in breast cancer treated with neoadjuvant CAF chemotherapy, 41% of tumours stained by senescence markers versus 10% of untreated cases; Adriamycin treatment for 5 days induced 60% of breast cancer cells to become senescent.
Senotherapies include senolytics (e.g., quercetin, navitoclax, fisetin) and senostatics (e.g., metformin); preclinical and early-phase data suggest potential to enhance cancer therapy and reduce frailty, but none are in routine clinical use.
Navitoclax is limited by toxicity, especially thrombocytopenia; dasatinib plus quercetin reduces senescent cells in models and improved physical dysfunction and lifespan in aged mice; fisetin is roughly twice as potent as quercetin, with an average daily dietary intake of 0.4 mg and a phase 2 trial using 20 mg/kg orally for 2 days.

Methods

Design: narrative review of the clinical implications of senescence and senotherapies in cancer.
Data/sample: published literature on senescence biology, cancer prognosis, chemotherapy, radiotherapy, hormonal therapy, surgery, frailty, and senotherapies, including preclinical mouse models and human cancer studies; no primary patient cohort is reported.
Main analysis: narrative synthesis with summary tables; no systematic search strategy, meta-analysis, or formal quality appraisal is described.

Limitations

Stated: the interactions between senescence and cancer are “complex and poorly understood,” and more research is needed to clarify them.
Stated: variation in SASP composition means findings may not be extrapolated to other cancers or treatment types; no senotherapies are yet approved for clinical use, and there are no published studies of senotherapies on acute wound healing.
Evident: as a narrative review, it does not describe a systematic literature search or formal evidence grading, and many cited data are preclinical, small, or early-phase.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/cancers12082134

Cites

123 of 123 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 84 cited sources checked · 0 supported · 0 flagged

In the paper
“This has been shown to suppress the progression of malignancy in hepatocytes in a mouse model [34].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 5. Role of Senescence in the Development of Cancer
What the sources say
- Not checked yetcites [34] Kang, 2011, Senescence surveillance of pre-malignant hepatocytes limits liver cancer development, Nature source
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In the paper
“This was shown in a study where telomere shortening in peripheral blood T cells, was linked to the development of cancer [37].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 5. Role of Senescence in the Development of Cancer
What the sources say
- Not checked yetcites [37] Falci, 2013, Immune senescence and cancer in elderly patients: Results from an exploratory study, Exp. Gerontol. source
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In the paper
“The treatment of breast cancer cells with Adriamycin for 5 days induces 60% of cells to become senescent [61].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 7. Role of Senescence in Cancer Treatment Response > Chemotherapy
What the sources say
- Not checked yetcites [61] You, R., Dai, J., Zhang, P., Barding, G.A., and Raftery, D. (2018). Dynamic Metabolic Response to Adriamycin-Induced Senescence in Breast Cancer Cells. Metabolites, 8. source
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In the paper
“Another study of a range of cancer types, including breast, lymphoma, colon, sarcoma and lung, found that senescence markers were linked to better prognosis [29].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 6. Role of Senescence as a Prognostic Marker for Cancer
What the sources say
- Not checked yetcites [29] Althubiti, 2014, Characterization of novel markers of senescence and their prognostic potential in cancer, Cell Death Dis. source
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In the paper
“Colon and endometrial cancers have also been studied, as well as senescence markers linked to improved prognosis [44,45].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 6. Role of Senescence as a Prognostic Marker for Cancer
What the sources say
- Not checked yetcites [44] Jung, 2001, The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, and p16INK4A and is a region of low proliferation, Am. J. Pathol. source
- Not checked yetcites [45] Horree, 2007, The invasive front in endometrial carcinoma: Higher proliferation and associated derailment of cell cycle regulators, Hum. Pathol. source
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In the paper
“In a mouse model, lymphomas induced by the myc oncogene responded to cyclophosphamide by undergoing senescence mediated by p16INK4A and p53 [57].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 7. Role of Senescence in Cancer Treatment Response > Chemotherapy
What the sources say
- Not checked yetcites [57] Schmitt, 2002, A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy, Cell source
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In the paper
“Another study of breast cancer demonstrated that the increased expressions of senescence markers p14ARF and p16INK4a were associated with increased risk of disease recurrence and poor survival outcomes [43].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 6. Role of Senescence as a Prognostic Marker for Cancer
What the sources say
- Not checked yetcites [43] Pare, 2016, Increased expression of senescence markers p14(ARF) and p16(INK4a) in breast cancer is associated with an increased risk of disease recurrence and poor survival outcome, Histopathology source
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In the paper
“Senescence is increasingly recognized as a heterogeneous group of cell states, depending on the type, degree, and duration of stimuli that triggered it [11].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 2. Biological Changes of Aging and Senescence
What the sources say
- Not checked yetcites [11] Salama, 2014, Cellular senescence and its effector programs, Genes Dev. source
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In the paper
“and may provide a pathway for disease recurrence after cancer therapy.”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > Abstract
What the sources say
- Not checked yetcites [20] Saleh, 2019, Tumor Cell Escape from Therapy-Induced Senescence as a Model of Disease Recurrence after Dormancy, Cancer Res. source
- Not checked yetcites [21] Bharadwaj, 2020, Senescence in polyploid giant cancer cells: A road that leads to chemoresistance, Cytokine Growth Factor Rev. source
- Not checked yetcites [22] Lee, 2019, The dynamic nature of senescence in cancer, Nat. Cell Biol. source
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Show all 42 claims

It may state two separate claims as one. 38
Probably not a substantial claim. 12

None of the sources cited for this claim have been checked yet.
In the paper
“Studies have demonstrated high levels of senescence in premalignant lesions and lower levels in invasive disease, suggesting a role for senescence in blocking malignant progression [2,31,32].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 5. Role of Senescence in the Development of Cancer
What the sources say
- Not checked yetcites [2] Collado, 2005, Tumour biology: Senescence in premalignant tumours, Nature source
- Not checked yetcites [31] Chen, 2005, Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis, Nature source
- Not checked yetcites [32] Michaloglou, 2005, BRAFE600-associated senescence-like cell cycle arrest of human naevi, Nature source
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In the paper
“In breast cancer cases treated with neoadjuvant chemotherapy, 41% of tumours were stained by senescence markers compared to only 10% of untreated cases, showing that senescence is induced by CAF (cyclophosphamide, Adriamycin, and fluorouracil) chemotherapy [53].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 7. Role of Senescence in Cancer Treatment Response > Chemotherapy
What the sources say
- Not checked yetcites [53] Okorokov, 2002, DNA damage is able to induce senescence in tumor cells in vitro and in vivo, Cancer Res.
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In the paper
“In breast cancer, p16 levels correlate with breast cancer subtype, proliferative status, and prognosis [42].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 6. Role of Senescence as a Prognostic Marker for Cancer
What the sources say
- Not checked yetcites [42] Shin, 2015, Expression of p16 and pRB in invasive breast cancer, Int. J. Clin. Exp. Pathol.
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In the paper
“Acute senescence is a short-term process, often triggered to limit an inflammatory response or physiological process, such as wound healing or embryological development [12].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 2. Biological Changes of Aging and Senescence
What the sources say
- Not checked yetcites [12] Davaapil, 2017, Conserved and novel functions of programmed cellular senescence during vertebrate development, Development
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease.”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > Abstract
What the sources say
- Not checked yetcites [18] Campisi, 2005, Senescent cells, tumor suppression, and organismal aging: Good citizens, bad neighbors, Cell source
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In the paper
“Chronic senescence is triggered by feedback loops when the senescent stimulus is prolonged, and may cause diseases such as atherosclerosis, arthritis, neurodegenerative disease, and diabetes [13] as well as effecting classical age-related decline in tissue function [14].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 2. Biological Changes of Aging and Senescence
What the sources say
- Not checked yetcites [13] Calcinotto, 2019, Cellular Senescence: Aging, Cancer, and Injury, Physiol. Rev. source
- Not checked yetcites [14] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat. Med. source
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In the paper
“Aging is integral to the causation of many cancers and also impacts on treatment response, prognosis, treatment allocation, and treatment tolerance.”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 1. An Aging Population and Cancer
What the sources say
- Not checked yetcites [6] Partridge, 2018, Facing up to the global challenges of ageing, Nature source
- Not checked yetcites [7] Hanahan, 2011, Hallmarks of cancer: The next generation, Cell source
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In the paper
“Senescent cells are rare in the tissues of young organisms but become more common as tissues age, especially in adipose tissue, muscle, and skin [10].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 2. Biological Changes of Aging and Senescence
What the sources say
- Not checked yetcites [10] Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell source
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In the paper
“Cells have a finite ability to replicate (the Hayflick Limit [26]) and once this limit is reached, they lose the ability to divide but remain alive and metabolically active as senescent cells.”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 3. Regulatory Pathway of Senescence > 3.1. Replicative Senescence
What the sources say
- Not checked yetcites [26] Hayflick, 1961, The serial cultivation of human diploid cell strains, Exp. Cell Res. source
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In the paper
“There are also potential interactions with cancer therapies, in particular, radiotherapy and chemotherapy, which may trigger either cell death at high doses or senescence at non-lethal doses.”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 2. Biological Changes of Aging and Senescence
What the sources say
- Not checked yetcites [20] Saleh, 2019, Tumor Cell Escape from Therapy-Induced Senescence as a Model of Disease Recurrence after Dormancy, Cancer Res. source
- Not checked yetcites [21] Bharadwaj, 2020, Senescence in polyploid giant cancer cells: A road that leads to chemoresistance, Cytokine Growth Factor Rev. source
- Not checked yetcites [22] Lee, 2019, The dynamic nature of senescence in cancer, Nat. Cell Biol. source
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In the paper
“In contrast there is also evidence that stromal cell senescence may have a tumour promoting effect in some models—this may be because of the proangiogenic influence of some components of SASP, such as vascular endothelial growth factor (VEGF) or the impact of senescent fibroblasts on adjacent tumour cells [17,36].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 5. Role of Senescence in the Development of Cancer
What the sources say
- Not checked yetcites [17] Coppe, 2006, Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence, J. Biol. Chem. source
- Not checked yetcites [36] Bavik, 2006, The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms, Cancer Res. source
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In the paper
“In turn, senescence may impact on these same pathways via positive or negative feedback loops as well as other intracellular pathways and extracellular processes, such as the immune modulation, inflammation [16], regulation, and maintenance of the extracellular matrix, and angiogenesis [17].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 2. Biological Changes of Aging and Senescence
What the sources say
- Not checked yetcites [16] Freund, 2010, Inflammatory networks during cellular senescence: Causes and consequences, Trends Mol. Med. source
- Not checked yetcites [17] Coppe, 2006, Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence, J. Biol. Chem. source
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In the paper
“No one marker alone is sufficient to identify senescence and most researchers use a panel of biomarkers, such as senescence-associated β-galactosidase, p21, and p16INK4A, as well as a number of other biomarkers, such as heterochromatin and proliferation markers (Table 1) combined [24] with a marker of cellular proliferation (Ki-67, for instance).”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 2. Biological Changes of Aging and Senescence
What the sources say
- Not checked yetcites [23] Gorgoulis, 2019, Cellular Senescence: Defining a Path Forward, Cell source
- Not checked yetcites [24] Matjusaitis, 2016, Biomarkers to identify and isolate senescent cells, Ageing Res. Rev. source
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In the paper
“There is also evidence that “immune senescence”, associated with the aging of the immune system in older age may contribute to the failure of immune surveillance and contribute to cancer development in older people.”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 5. Role of Senescence in the Development of Cancer
What the sources say
- Not checked yetcites [37] Falci, 2013, Immune senescence and cancer in elderly patients: Results from an exploratory study, Exp. Gerontol. source
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In the paper
“It has been proposed that, whilst senescence itself is largely tumour suppressive [18], the SASP of chronically senescent cells may promote tumour recurrence or progression [19].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 2. Biological Changes of Aging and Senescence
What the sources say
- Not checked yetcites [19] Campisi, 2011, Cellular senescence: A link between cancer and age-related degenerative disease?, Semin. Cancer Biol.
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In the paper
“Consequently, senescence induced by some cancer therapies may be harmful and promote tumour growth.”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 7. Role of Senescence in Cancer Treatment Response > Chemotherapy
What the sources say
- Not checked yetcites [55] Basisty, N., Kale, A., Jeon, O.H., Kuehnemann, C., Payne, T., Rao, C., Holtz, A., Shah, S., Sharma, V., and Ferrucci, L. (2020). A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol., 18. source
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In the paper
“the diabetic drug, metformin has senostatic properties and reduces the stimulatory effect of SASP intermediates on prostate cancer cells [123]”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 12. Senotherapies > 12.4. Metformin
What the sources say
- Not checked yetcites [123] Moiseeva, 2013, Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation, Aging Cell source
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In the paper
“They are also present in cancer and in premalignant lesions and have been evaluated as prognostic markers [41].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 6. Role of Senescence as a Prognostic Marker for Cancer
What the sources say
- Not checked yetcites [41] Pare, R., Soon, P.S., Shah, A., and Lee, C.S. (2019). Differential expression of senescence tumour markers and its implications on survival outcomes of breast cancer patients. PLoS ONE, 14. source
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In the paper
“Moderate chemotherapy doses are more likely to cause senescence and higher doses more likely to cause cell death [54].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 7. Role of Senescence in Cancer Treatment Response > Chemotherapy
What the sources say
- Not checked yetcites [54] Roninson, 2003, Tumor cell senescence in cancer treatment, Cancer Res.
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In the paper
“For example, doxorubicin prevents the resealing of the DNA double helix by inhibiting topoisomerase 2, which triggers a DDR and thereby may cause senescence [54].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 7. Role of Senescence in Cancer Treatment Response > Chemotherapy
What the sources say
- Not checked yetcites [54] Roninson, 2003, Tumor cell senescence in cancer treatment, Cancer Res.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There is another way in which senolytics may impact on cancer outcomes—by enhancing resilience and reducing frailty.”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 13. Impact of Frailty on Cancer Treatment and Outcomes
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- Rests on an assumption: Long-term survivors of cancer have increased rates of frailty and reduced longevity.
- Rests on an assumption: Some of the increased frailty and reduced longevity in long-term cancer survivors is due to direct and indirect induction of senescent cells by cancer therapies (chemotherapy and radiotherapy).
- Rests on an assumption: Treatments such as surgery and chemotherapy have a significant negative impact on physical function, with studies showing an increase in measures of frailty after treatment, which may never recover back to baseline levels.
- Rests on an assumption: This loss of function is one of the reasons that older patients require longer hospital admission after surgery and sometimes require social care support in the longer term after surgery.
- Rests on an assumption: Physical dysfunction is a major burden on both the NHS and social care resources and is a research priority for the UK government.
In the paper
“Many types of chemotherapy cause DNA damage (DNA strand breaks or cross linking), which can, if severe, cause cell death via the DNA damage response, or they may trigger a non-lethal DDR, leading to acute or chronic senescence, depending on the extent and duration of the stimulus [52].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 7. Role of Senescence in Cancer Treatment Response > Chemotherapy
What the sources say
- Not checked yetcites [52] 2014, The role of senescent cells in ageing, Nature source
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In the paper
“In terms of clinical trials, this 100 mg dose has been used in a colorectal cancer chemotherapy study and has been shown to reduce inflammatory markers, although numbers were small and no clinical cancer end points were assessed [121].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 12. Senotherapies > 12.3. Fisetin
What the sources say
- Not checked yetcites [121] Alizadeh, 2018, Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients, Food Funct. source
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None of the sources cited for this claim have been checked yet.
In the paper
“Senescence is also an important mechanism of efficacy in the treatment of breast cancer with PARP inhibitors [59] and many typical chemotherapy agents used to treat breast cancer, such as epirubicin and cyclophosphamide [60].”
§ Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies > 7. Role of Senescence in Cancer Treatment Response > Chemotherapy
What the sources say
- Not checked yetcites [59] Fleury, 2019, Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence, Nat. Commun. source
- Not checked yetcites [60] Munoz, D.P., Yannone, S.M., Daemen, A., Sun, Y., Vakar-Lopez, F., Kawahara, M., Freund, A.M., Rodier, F., Wu, J.D., and Desprez, P.Y. (2019). Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging. JCI Insight, 5. source
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47 of 47

The paper relies on this without support.
Findings from mouse models of senescence and senotherapy are informative for human cancer treatment.
“This principle was elegantly demonstrated in a mouse model, where the implantation of senescent cells into young mice induced physical dysfunction, which spread beyond the injected senescent cells and reduced lifespan.”
“In a separate study, again in a mouse model, the elimination of senescent cells by the use of dasatinib and quercetin, reduced the impact of radiotherapy, improved cardiac function and exercise tolerance and increased life expectancy [90].”
The paper relies on this without support.
Senescence biomarkers used in human studies reliably identify senescent cells in tumours.
“The detection of senescence is complicated, as many of the molecules involved in senescence signalling are also oncogenes or tumour suppressors that may be up or down regulated as part of the carcinogenic process.”
“The assessment of combinations of markers is therefore required in addition to a marker of proliferation, such as Ki67.”
The paper relies on this without support.
Long-term survivors of cancer have increased rates of frailty and reduced longevity.
“It is already recognised that long-term survivors of cancer have increased rates of frailty and reduced longevity”
The paper relies on this without support.
Some of the increased frailty and reduced longevity in long-term cancer survivors is due to direct and indirect induction of senescent cells by cancer therapies (chemotherapy and radiotherapy).
“some of which are thought to be due to the direct and indirect induction of senescent cells by cancer therapies (chemotherapy and radiotherapy).”
The paper relies on this without support.
Treatments such as surgery and chemotherapy have a significant negative impact on physical function, with studies showing an increase in measures of frailty after treatment, which may never recover back to baseline levels.
“It is well recognized that treatments such as surgery and chemotherapy have a significant negative impact on physical function, with studies showing an increase in measures of frailty after treatment, which may never recover back to baseline levels.”
The paper relies on this without support.
This loss of function is one of the reasons that older patients require longer hospital admission after surgery and sometimes require social care support in the longer term after surgery.
“This loss of function is one of the reasons that older patients require longer hospital admission after surgery and sometimes require social care support in the longer term after surgery.”
The paper relies on this without support.
Physical dysfunction is a major burden on both the NHS and social care resources and is a research priority for the UK government.
“This physical dysfunction is therefore a major burden on both the NHS and social care resources and is a research priority for the UK government.”

7 of 7

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Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · cited 1×
“Aging interacts with cancer in a range of ways: some of the molecular pathways and causes of aging [6] and the pathways and causes of cancer [7] overlap significantly.”
Background
The Hallmarks of Aging
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982 · cited 1×
“Aging is a complex process involving multiple factors, including genetic and epigenetic alterations to DNA, cellular damage from reactive oxygen species (ROS) produced by incomplete aerobic metabolism, age-dependent decline in mitochondrial function, stem cell exhaustion, and telomere shortening [6,8].”
Background
The serial cultivation of human diploid cell strains
Hayflick, L., & Moorhead, P. S. (1961) · Experimental Cell Research · doi:10.1016/0014-4827(61)90192-6 · Cited by 8,508 · cited 2×
“Cells have a finite ability to replicate (the Hayflick Limit [26]) and once this limit is reached, they lose the ability to divide but remain alive and metabolically active as senescent cells.”
Background
Factors affecting wound healing
Guo, S., & DiPietro, L. A. (2010) · Journal of Dental Research · doi:10.1177/0022034509359125 · Cited by 5,792 · cited 1×
“Wound healing is impaired in older organisms [82] for a variety of reasons and it is known that the skin is an area where senescent cells accumulate with age.”
Background
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218
Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases
Franceschi, C., & Campisi, J. (2014) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glu057 · Cited by 3,891 · cited 1×
“Biomarkers of frailty are generally linked to the presence of chronic low grade inflammation [88] and a range of inflammatory markers have been studied and correlate with poor treatment outcomes across a range of diseases [89].”
Background
Cellular Senescence: Defining a Path Forward
Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.005 · Cited by 3,225 · cited 2×
“Consequently, there is great academic interest in senescence, and researchers have developed reliable methods to identify these cells in tissue sections [23].”
BackgroundMethod
Broken Limits to Life Expectancy
Oeppen, J., & Vaupel, J. W. (2002) · Science · doi:10.1126/science.1069675 · Cited by 2,819 · cited 1×
“In the western world, life-expectancy has doubled in the past 200 years and, whilst most of the early gains were in childhood longevity, in the past 70 years the majority of gains have been in older people [1,2].”
The role of senescent cells in ageing
van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623
The Achilles' heel of senescent cells: from transcriptome to senolytic drugs
Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., et al. (2015) · Aging Cell · doi:10.1111/acel.12344 · Cited by 2,584 · cited 3×
“It reduces levels of senescent cells in a range of in vitro models and in mouse in vivo models [14,90].”
BackgroundSelf-citation
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,379 · cited 1×
“It has been proposed that, whilst senescence itself is largely tumour suppressive [18], the SASP of chronically senescent cells may promote tumour recurrence or progression [19].”
Background
Senolytics improve physical function and increase lifespan in old age
Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., Inman, C. L., Ogrodnik, M. B., Hachfeld, C. M., Fraser, D. G., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0092-9 · Cited by 2,287 · cited 7×
“While D + Q has been shown to reduce levels of senescent cells in a range of in vitro models and in mouse in vivo models [14,90], to date there are few clinical trial data of its efficacy in the cancer setting, although some evidence in non-cancer settings.”
BackgroundInfluentialSelf-citation
BRAFE600-associated senescence-like cell cycle arrest of human naevi
Michaloglou, C., Vredeveld, L. C. W., Soengas, M. S., Denoyelle, C., Kuilman, T., van der Horst, C. M. A. M., Majoor, D. M., Shay, J. W., Mooi, W. J., & Peeper, D. S. (2005) · Nature · doi:10.1038/nature03890 · Cited by 2,160 · cited 1×
“Studies have demonstrated high levels of senescence in premalignant lesions and lower levels in invasive disease, suggesting a role for senescence in blocking malignant progression [2,31,32].”
Background
An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA
Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M. E. T., et al. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.11.012 · Cited by 2,045
Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis
Chen, Z., Trotman, L. C., Shaffer, D., Lin, H.-K., Dotan, Z. A., Niki, M., Koutcher, J. A., Scher, H. I., Ludwig, T., Gerald, W., et al. (2005) · Nature · doi:10.1038/nature03918 · Cited by 1,993 · cited 2×
“Studies have demonstrated high levels of senescence in premalignant lesions and lower levels in invasive disease, suggesting a role for senescence in blocking malignant progression [2,31,32].”
Background
ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor
Tse, C., Shoemaker, A. R., Adickes, J., Anderson, M. G., Chen, J., Jin, S., Johnson, E. F., Marsh, K. C., Mitten, M. J., Nimmer, P., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5836 · Cited by 1,992 · cited 2×
“Navitoclax interacts with the BCL-2 pathway and prevents it from inhibiting apoptosis, causing the senescent cells to undergo apoptosis [91].”
Background
Senescence surveillance of pre-malignant hepatocytes limits liver cancer development
Kang, T.-W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011) · Nature · doi:10.1038/nature10599 · Cited by 1,621 · cited 1×
“This has been shown to suppress the progression of malignancy in hepatocytes in a mouse model [34].”
Background
Cellular senescence mediates fibrotic pulmonary disease
Schafer, M. J., White, T. A., Iijima, K., Haak, A. J., Ligresti, G., Atkinson, E. J., Oberg, A. L., Birch, J., Salmonowicz, H., Zhu, Y., et al. (2017) · Nature Communications · doi:10.1038/ncomms14532 · Cited by 1,613
Self-citation
Ink4a/Arf expression is a biomarker of aging
Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22475 · Cited by 1,486
Senescence in premalignant tumours
Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A. J., Barradas, M., Benguría, A., Zaballos, A., Flores, J. M., Barbacid, M., et al. (2005) · Nature · doi:10.1038/436642a · Cited by 1,482
Facing up to the global challenges of ageing
Partridge, L., Deelen, J., & Slagboom, P. E. (2018) · Nature · doi:10.1038/s41586-018-0457-8 · Cited by 1,475 · cited 2×
“Aging is a complex process involving multiple factors, including genetic and epigenetic alterations to DNA, cellular damage from reactive oxygen species (ROS) produced by incomplete aerobic metabolism, age-dependent decline in mitochondrial function, stem cell exhaustion, and telomere shortening [6,8].”
Background
Inflammatory networks during cellular senescence: causes and consequences.
Freund, A., Orjalo, A. V., Desprez, P.-Y., & Campisi, J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.03.003 · Cited by 1,354 · cited 1×
“In turn, senescence may impact on these same pathways via positive or negative feedback loops as well as other intracellular pathways and extracellular processes, such as the immune modulation, inflammation [16], regulation, and maintenance of the extracellular matrix, and angiogenesis [17].”
Background
A proteomic atlas of senescence-associated secretomes for aging biomarker development
Basisty, N., Kale, A., Jeon, O. H., Kuehnemann, C., Payne, T., Rao, C., Holtz, A., Shah, S., Sharma, V., Ferrucci, L., et al. (2020) · PLOS Biology · doi:10.1371/journal.pbio.3000599 · Cited by 1,348 · cited 3×
“In particular, some senescent cells secrete exosomes [56] (small “packages” containing a variety of proteins and mRNA) and these may have a tumour promoter function [55].”
Background
Cellular senescence promotes adverse effects of chemotherapy and cancer relapse
Demaria, M., O'Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., Koenig, K., Le, C., Mitin, N., Deal, A. M., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0241 · Cited by 1,338 · cited 4×
“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].”
BackgroundInfluential
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270 · cited 2×
“Chronic senescence is triggered by feedback loops when the senescent stimulus is prolonged, and may cause diseases such as atherosclerosis, arthritis, neurodegenerative disease, and diabetes [13] as well as effecting classical age-related decline in tissue function [14].”
Background
Mechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232 · cited 1×
“The regulation of senescence is complex and incompletely understood, and a detailed review is beyond the scope of this article, but excellent reviews are available [13,25].”
Background
Oncogene-induced senescence as an initial barrier in lymphoma development
Braig, M., Lee, S., Loddenkemper, C., Rudolph, C., Peters, A. H. F. M., Schlegelberger, B., Stein, H., Dörken, B., Jenuwein, T., & Schmitt, C. A. (2005) · Nature · doi:10.1038/nature03841 · Cited by 1,220 · cited 1×
“Similarly, senescence has been seen in chemotherapy-treated lymphoma [64].”
Background
Targeting cellular senescence prevents age-related bone loss in mice
Farr, J. N., Xu, M., Weivoda, M. M., Monroe, D. G., Fraser, D. G., Onken, J. L., Negley, B. A., Sfeir, J. G., Ogrodnik, M. B., Hachfeld, C. M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4385 · Cited by 1,182
Self-citation
Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors
Zhu, Y., Tchkonia, T., Fuhrmann‐Stroissnigg, H., Dai, H. M., Ling, Y. Y., Stout, M. B., Pirtskhalava, T., Giorgadze, N., Johnson, K. O., Giles, C. B., et al. (2016) · Aging Cell · doi:10.1111/acel.12445 · Cited by 1,148 · cited 1×
“Navitoclax interacts with the BCL-2 pathway and prevents it from inhibiting apoptosis, causing the senescent cells to undergo apoptosis [91].”
BackgroundSelf-citation
Senescence-associated reprogramming promotes cancer stemness
Milanovic, M., Fan, D. N. Y., Belenki, D., Däbritz, J. H. M., Zhao, Z., Yu, Y., Dörr, J. R., Dimitrova, L., Lenze, D., Monteiro Barbosa, I. A., et al. (2018) · Nature · doi:10.1038/nature25167 · Cited by 1,131
Senescence in tumours: evidence from mice and humans
Collado, M., & Serrano, M. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2772 · Cited by 1,124 · cited 1×
“Other mechanisms of tumour suppression have been proposed [35].”
Background
Fat tissue, aging, and cellular senescence
Tchkonia, T., Morbeck, D. E., Von Zglinicki, T., Van Deursen, J., Lustgarten, J., Scrable, H., Khosla, S., Jensen, M. D., & Kirkland, J. L. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00608.x · Cited by 1,094 · cited 1×
“Senescent cells are rare in the tissues of young organisms but become more common as tissues age, especially in adipose tissue, muscle, and skin [10].”
BackgroundSelf-citation
A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy
Schmitt, C. A., Fridman, J. S., Yang, M., Lee, S., Baranov, E., Hoffman, R. M., & Lowe, S. W. (2002) · Cell · doi:10.1016/s0092-8674(02)00734-1 · Cited by 1,050 · cited 1×
“In a mouse model, lymphomas induced by the myc oncogene responded to cyclophosphamide by undergoing senescence mediated by p16INK4A and p53 [57].”
Background
Fisetin is a senotherapeutic that extends health and lifespan
Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.015 · Cited by 1,032
Self-citation
The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing
Jun, J.-I., & Lau, L. F. (2010) · Nature Cell Biology · doi:10.1038/ncb2070 · Cited by 998 · cited 1×
“Matrix metalloproteinases within the SASP help to degrade collagen as part of remodelling [79].”
Background
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855 · cited 1×
“Senescence is increasingly recognized as a heterogeneous group of cell states, depending on the type, degree, and duration of stimuli that triggered it [11].”
Background
Therapy-induced senescence in cancer.
Ewald, J. A., Desotelle, J. A., Wilding, G., & Jarrard, D. F. (2010) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djq364 · Cited by 824 · cited 1×
“It has been hypothesised that the induction of permanent senescent cytostasis may be an effective strategy for cancer treatment, rather than killing the cancer cell [58], and may have reduced toxicity.”
Background
Lifespan and healthspan: past, present, and promise
Crimmins, E. M. (2015) · The Gerontologist · doi:10.1093/geront/gnv130 · Cited by 762 · cited 1×
“Consequently, life-span has outpaced health-span [4], as the burden of chronic health conditions has increased in this older population.”
Background
New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463
Zhu, Y., Doornebal, E. J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., Niedernhofer, L. J., Robbins, P. D., Tchkonia, T., & Kirkland, J. L. (2017) · Aging · doi:10.18632/aging.101202 · Cited by 757
Self-citation
Global cancer incidence in older adults, 2012 and 2035: A population‐based study
Pilleron, S., Sarfati, D., Janssen-Heijnen, M. L. G., Vignat, J., Ferlay, J., Bray, F., & Soerjomataram, I. (2018) · International Journal of Cancer · doi:10.1002/ijc.31664 · Cited by 672
Metformin inhibits the senescence‐associated secretory phenotype by interfering with IKK/NF‐κ B activation
Moiseeva, O., Deschênes‐Simard, X., St‐Germain, E., Igelmann, S., Huot, G., Cadar, A. E., Bourdeau, V., Pollak, M. N., & Ferbeyre, G. (2013) · Aging Cell · doi:10.1111/acel.12075 · Cited by 654
Untitled work
(2002) · PubMed · Cited by 640
Untitled work
(2003) · PubMed · Cited by 608
Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence
Coppé, J.-P., Kauser, K., Campisi, J., & Beauséjour, C. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603307200 · Cited by 604 · cited 1×
“In turn, senescence may impact on these same pathways via positive or negative feedback loops as well as other intracellular pathways and extracellular processes, such as the immune modulation, inflammation [16], regulation, and maintenance of the extracellular matrix, and angiogenesis [17].”
Background
The 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
Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer
Rudin, C. M., Hann, C. L., Garon, E. B., de Oliveira, M. R., Bonomi, P., Camidge, D. R., Chu, Q. S.-C., Giaccone, G., Khaira, D. K., Ramalingam, S. S., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-3090 · Cited by 576
Accumulation of senescent cells in Mitotic tissue of aging primates
Jeyapalan, J. C., Ferreira, M., Sedivy, J. M., & Herbig, U. (2007) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2006.11.008 · Cited by 571
Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis
Sarkisian, C. J., Keister, B. A., Stairs, D. B., Boxer, R. B., Moody, S. E., & Chodosh, L. A. (2007) · Nature Cell Biology · doi:10.1038/ncb1567 · Cited by 490
Senescence-Associated Exosome Release from Human Prostate Cancer Cells
Lehmann, B. D., Paine, M. S., Brooks, A. M., McCubrey, J. A., Renegar, R. H., Wang, R., & Terrian, D. M. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6538 · Cited by 464 · cited 1×
“In particular, some senescent cells secrete exosomes [56] (small “packages” containing a variety of proteins and mRNA) and these may have a tumour promoter function [55].”
Background
Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis
Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy., K. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.08.003 · Cited by 455 · cited 1×
“For example, the diabetic drug, metformin has senostatic properties and reduces the stimulatory effect of SASP intermediates on prostate cancer cells [123] and is effective in reducing the incidence (chemoprevention) of a range of different cancers [124].”
Background
The Gene Expression Program of Prostate Fibroblast Senescence Modulates Neoplastic Epithelial Cell Proliferation through Paracrine Mechanisms
Bavik, C., Coleman, I., Dean, J. P., Knudsen, B., Plymate, S., & Nelson, P. S. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-1716 · Cited by 453
Escape from Therapy-Induced Accelerated Cellular Senescence in p53-Null Lung Cancer Cells and in Human Lung Cancers
Roberson, R. S., Kussick, S. J., Vallieres, E., Chen, S.-Y. J., & Wu, D. Y. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-1270 · Cited by 428 · cited 2×
“in patients with non-small cell lung cancer showed increased senescence biomarkers in patients treated with a taxane and carboplatin [62].”
Background
Cellular senescence: a link between cancer and age-related degenerative disease?
Campisi, J., Andersen, J. K., Kapahi, P., & Melov, S. (2011) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2011.09.001 · Cited by 421 · cited 1×
“It has been proposed that, whilst senescence itself is largely tumour suppressive [18], the SASP of chronically senescent cells may promote tumour recurrence or progression [19].”
Background
A meta-analysis of genome-wide association studies identifies multiple longevity genes
Deelen, J., Evans, D. S., Arking, D. E., Tesi, N., Nygaard, M., Liu, X., Wojczynski, M. K., Biggs, M. L., van der Spek, A., Atzmon, G., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11558-2 · Cited by 370 · cited 1×
“The rate at which aging occurs is highly variable and depends on both polygenic hereditary factors [9] and a wide range of environmental factors (such as obesity, diet, exercise, and exposure to drugs and chemicals), which is why biological and chronological age are often mis-matched.”
Background
The unfolded protein response and cellular senescence. A Review in the Theme: Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease
Pluquet, O., Pourtier, A., & Abbadie, C. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00334.2014 · Cited by 305 · cited 3×
“Metabolic stress may also induce senescence and trigger the unfolded protein response (UPR).”
Background
Galacto‐conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity
González‐Gualda, E., Pàez‐Ribes, M., Lozano‐Torres, B., Macias, D., Wilson, J. R., González‐López, C., Ou, H., Mirón‐Barroso, S., Zhang, Z., Lérida‐Viso, A., et al. (2020) · Aging Cell · doi:10.1111/acel.13142 · Cited by 303 · cited 2×
“As senescent cells have higher levels of the galactosidase enzyme (SA β-galactosidase), the release of active Navitoclax is targeted to the senescent cells, potentially reducing platelet toxicity [93].”
Background
Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor
Coppé, J.-P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060301 · Cited by 302 · cited 1×
“Similarly, in prostate cancers treated with neoadjuvant mitozantrone, elevated levels of senescence biomarkers were found [31,63].”
Background
Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies
Tchkonia, T., & Kirkland, J. L. (2018) · JAMA · doi:10.1001/jama.2018.12440 · Cited by 302
Self-citation
The number of p16INK4a positive cells in human skin reflects biological age
Waaijer, M. E. C., Parish, W. E., Strongitharm, B. H., van Heemst, D., Slagboom, P. E., de Craen, A. J. M., Sedivy, J. M., Westendorp, R. G. J., Gunn, D. A., & Maier, A. B. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00837.x · Cited by 264
Tumor cell escape from therapy-induced senescence as a model of disease recurrence after dormancy.
Saleh, T., Tyutyunyk-Massey, L., & Gewirtz, D. A. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3437 · Cited by 259 · cited 1×
“There is evidence that senescent cells may also be re-programmed to re-enter the cell cycle after certain types of chemotherapy [20,21,62] and may acquire a more “stem cell”-like phenotype, which may in turn contribute to tumour regrowth and evolution [66,67].”
Background
Characterization of novel markers of senescence and their prognostic potential in cancer
Althubiti, M., Lezina, L., Carrera, S., Jukes-Jones, R., Giblett, S. M., Antonov, A., Barlev, N., Saldanha, G. S., Pritchard, C. A., Cain, K., et al. (2014) · Cell Death & Disease · doi:10.1038/cddis.2014.489 · Cited by 256 · cited 1×
“Another study of a range of cancer types, including breast, lymphoma, colon, sarcoma and lung, found that senescence markers were linked to better prognosis [29].”
Background
Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence
Fleury, H., Malaquin, N., Tu, V., Gilbert, S., Martinez, A., Olivier, M.-A., Sauriol, S. A., Communal, L., Leclerc-Desaulniers, K., Carmona, E., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10460-1 · Cited by 228 · cited 1×
“Senescence is also an important mechanism of efficacy in the treatment of breast cancer with PARP inhibitors [59] and many typical chemotherapy agents used to treat breast cancer, such as epirubicin and cyclophosphamide [60].”
Background
The Invasion Front of Human Colorectal Adenocarcinomas Shows Co-Localization of Nuclear β-Catenin, Cyclin D1, and p16INK4A and Is a Region of Low Proliferation
Jung, A., Schrauder, M., Oswald, U., Knoll, C., Sellberg, P., Palmqvist, R., Niedobitek, G., Brabletz, T., & Kirchner, T. (2001) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63007-6 · Cited by 217 · cited 1×
“Colon and endometrial cancers have also been studied, as well as senescence markers linked to improved prognosis [44,45].”
Background
A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia
Kipps, T. J., Eradat, H. A., Grosicki, S., Catalano, J. V., Cosolo, W., Dyagil, I., Yalamanchili, S., Chai, A., Sahasranaman, S., Punnoose, E. A., et al. (2015) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2015.1030638 · Cited by 196 · cited 1×
“2015 [100] Phase 2 clinical trial Rituximab+Navitoclax Chronic lymphocytic lymphoma Combination increase progression free survival and response rates”
Background
Polyploid giant cancer cells: Unrecognized actuators of tumorigenesis, metastasis, and resistance
Amend, S. R., Torga, G., Lin, K.-C., Kostecka, L. G., Marzo, A. D., Austin, R. H., & Pienta, K. J. (2019) · The Prostate · doi:10.1002/pros.23877 · Cited by 190
Roles of Polyploid/Multinucleated Giant Cancer Cells in Metastasis and Disease Relapse Following Anticancer Treatment
Mirzayans, R., Andrais, B., & Murray, D. L. (2018) · Cancers · doi:10.3390/cancers10040118 · Cited by 182
Senescence and the healing rates of venous ulcers
Stanley, A. C., & Osler, T. M. (2001) · Journal of Vascular Surgery · doi:10.1067/mva.2001.115379 · Cited by 170 · cited 1×
“Levels of senescent fibroblasts are correlated with the length of time taken by venous ulcers to heal [81].”
Background
Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging
Muñoz, D. P., Yannone, S. M., Daemen, A., Sun, Y., Vakar-Lopez, F., Kawahara, M., Freund, A. M., Rodier, F., Wu, J. D., Desprez, P.-Y., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.124716 · Cited by 162 · cited 1×
“Senescence is also an important mechanism of efficacy in the treatment of breast cancer with PARP inhibitors [59] and many typical chemotherapy agents used to treat breast cancer, such as epirubicin and cyclophosphamide [60].”
Background
Discovery, development, and future application of senolytics: theories and predictions
Wissler Gerdes, E. O., Zhu, Y., Tchkonia, T., & Kirkland, J. L. (2020) · The FEBS Journal · doi:10.1111/febs.15264 · Cited by 160
Self-citation
Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways
Jia, S., Xu, X., Zhou, S., Chen, Y., Ding, G., & Cao, L. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1366-y · Cited by 158
Fisetin: A bioactive phytochemical with potential for cancer prevention and pharmacotherapy
Kashyap, D., Sharma, A. K., Sak, K., Tuli, H. S., Buttar, H. S., & Bishayee, A. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.12.005 · Cited by 154
Biomarkers to identify and isolate senescent cells
Matjusaitis, M., Chin, G., Sarnoski, E. A., & Stolzing, A. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.05.003 · Cited by 144 · cited 1×
“No one marker alone is sufficient to identify senescence and most researchers use a panel of biomarkers, such as senescence-associated β-galactosidase, p21, and p16INK4A, as well as a number of other biomarkers, such as heterochromatin and proliferation markers (Table 1) combined [24] with a marker of cellular prolife…”
Background
Elevated Local Senescence in Diabetic Wound Healing Is Linked to Pathological Repair via CXCR2
Wilkinson, H. N., Clowes, C., Banyard, K. L., Matteuci, P., Mace, K. A., & Hardman, M. J. (2019) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2019.01.005 · Cited by 138
Markers of cellular senescence in zero hour biopsies predict outcome in renal transplantation
Koppelstaetter, C., Schratzberger, G., Perco, P., Hofer, J., Mark, W., Öllinger, R., Oberbauer, R., Schwarz, C., Mitterbauer, C., Kainz, A., et al. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2008.00398.x · Cited by 124 · cited 1×
“Few studies have directly assessed the relationship with senescence and surgical outcomes; however, p16 expression is negatively correlated with liver regeneration after hepatectomy in older patients [83] and the molecular aging marker CDKN2A has been shown to predict renal allograft function after 1 year in renal tra…”
Background
Conserved and novel functions of programmed cellular senescence during vertebrate development
Davaapil, H., Brockes, J. P., & Yun, M. H. (2016) · Development · doi:10.1242/dev.138222 · Cited by 124 · cited 2×
“Acute senescence is a short-term process, often triggered to limit an inflammatory response or physiological process, such as wound healing or embryological development [12].”
Background
How fisetin reduces the impact of age and disease on CNS function
Maher, P. A. (2015) · Frontiers in Bioscience-Scholar · doi:10.2741/s425 · Cited by 118
Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer MCF-7 cells by induction of caspase-7-associated apoptosis and inhibition of autophagy
Chiu, S.-J. (2011) · International Journal of Oncology · doi:10.3892/ijo.2011.1203 · Cited by 115
Cellular senescence and radiation-induced pulmonary fibrosis
He, Y., Thummuri, D., Zheng, G., Okunieff, P. G., Citrin, D. E., Vujašković, Ž., & Zhou, D. (2019) · Translational research · doi:10.1016/j.trsl.2019.03.006 · Cited by 107 · cited 1×
“This can be a potentially severe complication of radiotherapy, especially in the lung where pulmonary fibrosis may occur [74].”
Background
Improved antiangiogenic and antitumour activity of the combination of the natural flavonoid fisetin and cyclophosphamide in Lewis lung carcinoma-bearing mice
Touil, Y. S., Séguin, J., Scherman, D., & Chabot, G. G. (2010) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-010-1505-8 · Cited by 106
Navitoclax Enhances the Efficacy of Taxanes in Non–Small Cell Lung Cancer Models
Tan, N., Malek, M., Zha, J., Peng, Y., Kassees, R., Berry, L., Fairbrother, W. J., Sampath, D., & Belmont, L. D. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2353 · Cited by 106 · cited 1×
“2011 [94] In vitro Naviticlax+Paclitaxel Non-small cell lung cancer More than additive cell killing with combination”
Background
The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways
Youns, M., & Hegazy, W. A. H. (2017) · PLoS ONE · doi:10.1371/journal.pone.0169335 · Cited by 103
Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients
Farsad-Naeimi, A., Alizadeh, M., Esfahani, A., & Darvish Aminabad, E. (2018) · Food & Function · doi:10.1039/c7fo01898c · Cited by 95 · cited 2×
“, 2018 [121] Randomised clinical trial of dietary supplement dose of Fisetin Oxaliplatin and capecitabine chemotherapy ± Fisetin 100 mg daily for 7 weeks Colorectal cancer Reduced levels of inflammatory mediators (IL8, CRP and MMP7) in Fisetin group.”
Background
Hsp90 inhibitors as senolytic drugs to extend healthy aging
Fuhrmann-Stroissnigg, H., Niedernhofer, L. J., & Robbins, P. D. (2018) · Cell Cycle · doi:10.1080/15384101.2018.1475828 · Cited by 92
Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells
Pal, H. C., Baxter, R. D., Hunt, K. M., Agarwal, J., Elmets, C. A., Athar, M., & Afaq, F. (2015) · Oncotarget · doi:10.18632/oncotarget.5064 · Cited by 91
Immune recognition of irradiated cancer cells
Wennerberg, E., Vanpouille‐Box, C., Bornstein, S., Yamazaki, T., Demaria, S., & Galluzzi, L. (2017) · Immunological Reviews · doi:10.1111/imr.12568 · Cited by 88 · cited 1×
“In contrast, radiotherapy also triggers an immune response, making the treated cells more immunogenic in a variety of ways [73].”
Background
Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2
Pernicová, Z., Slabáková, E., Kharaishvili, G., Bouchal, J., Král, M., Kunická, Z., Machala, M., Kozubı́k, A., & Souček, K. (2011) · Neoplasia · doi:10.1593/neo.11182 · Cited by 87 · cited 1×
“Similarly androgen deprivation therapy induces senescence in prostate cancer cells and the SASP has been implicated in disease progression [77].”
Background
Senolytics (DQ) Mitigates Radiation Ulcers by Removing Senescent Cells
Wang, H., Wang, Z., Huang, Y., Zhou, Y., Sheng, X., Jiang, Q., Wang, Y., Luo, P., Luo, M., & Shi, C. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01576 · Cited by 84 · cited 4×
“Senescent cells also appear to be linked to skin fibrosis and ulceration following radiotherapy [75].”
BackgroundInfluential
Radiation-induced homotypic cell fusions of innately resistant glioblastoma cells mediate their sustained survival and recurrence
Kaur, E., Rajendra, J., Jadhav, S., Shridhar, E., Goda, J. S., Moiyadi, A. V., & Dutt, S. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv050 · Cited by 82 · cited 1×
“Cerebral glioblastoma, in which radiotherapy induces senescent multinucleate giant cells to form and reactivate these cells, is now recognized as an important mechanism of relapse [72].”
Background
Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal Pathway
Li, J., Gong, X., Jiang, R., Lin, D. C.-C., Zhou, T., Zhang, A., Li, H., Zhang, X., Wan, J., Kuang, G., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00772 · Cited by 79
The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence
Haferkamp, S., Tran, S. L., Becker, T. M., Scurr, L. L., Kefford, R. F., & Rizos, H. (2009) · Aging · doi:10.18632/aging.100051 · Cited by 77
Premature aging/senescence in cancer cells facing therapy: good or bad?
Calvo, L., Ghadaouia, S., Martinez, A., & Rodier, F. (2015) · Biogerontology · doi:10.1007/s10522-015-9593-9 · Cited by 74 · cited 1×
“Whilst cells that undergo apoptosis are permanently removed from a cancer, senescent cells remain and secrete various inflammatory cytokines, which may have both positive and negative impacts [65].”
Background
Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway
Lin, M.-T., Lin, C., Lin, T., Cheng, C., Yang, S., Lin, C., Wu, C., Hsieh, Y., & Tsai, J. (2015) · Tumor Biology · doi:10.1007/s13277-015-4526-4 · Cited by 69
The unfolded protein response and cancer: A brighter future unfolding?
Scriven, P., Brown, N. J., Pockley, A. G., & Wyld, L. (2007) · Journal of Molecular Medicine · doi:10.1007/s00109-006-0150-5 · Cited by 67 · cited 1×
“The UPR is often activated in many cancers [27] due to their abnormal microcirculation (which leads to cellular hypoxia and acidosis) and the high glucose needs of tumours (Warberg effect), resulting in metabolic stress.”
BackgroundSelf-citation
Senescence in polyploid giant cancer cells: A road that leads to chemoresistance
Bharadwaj, D., & Mandal, M. (2020) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2019.11.002 · Cited by 64 · cited 1×
“There is evidence that senescent cells may also be re-programmed to re-enter the cell cycle after certain types of chemotherapy [20,21,62] and may acquire a more “stem cell”-like phenotype, which may in turn contribute to tumour regrowth and evolution [66,67].”
Background
Premature senescence in human breast cancer and colon cancer cells by tamoxifen-mediated reactive oxygen species generation
Lee, Y., Kang, B. S., & Bae, Y. (2013) · Life Sciences · doi:10.1016/j.lfs.2013.12.009 · Cited by 63 · cited 1×
“The mechanism of action of antioestrogen therapies in breast cancer and the mechanisms of resistance are very complex, but senescence may be one of the pathways activated when disease responds to antioestrogens [76].”
Background
Cell-in-cell structures are more potent predictors of outcome than senescence or apoptosis in head and neck squamous cell carcinomas
Schenker, H., Büttner-Herold, M. J., Fietkau, R., & Distel, L. V. (2017) · Radiation Oncology · doi:10.1186/s13014-016-0746-z · Cited by 56
The invasive front in endometrial carcinoma: Higher proliferation and associated derailment of cell cycle regulators
Horrée, N., van Diest, P. J., Sie-Go, D. M. D. S., & Heintz, A. P. M. (2007) · Human Pathology · doi:10.1016/j.humpath.2007.01.008 · Cited by 53 · cited 1×
“Colon and endometrial cancers have also been studied, as well as senescence markers linked to improved prognosis [44,45].”
Background
Immune senescence and cancer in elderly patients: Results from an exploratory study
Falci, C., Gianesin, K., Sergi, G., Giunco, S., De Ronch, I., Valpione, S., Soldà, C., Fiduccia, P., Lonardi, S., Zanchetta, M., et al. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2013.09.011 · Cited by 46 · cited 1×
“This was shown in a study where telomere shortening in peripheral blood T cells, was linked to the development of cancer [37].”
Background
Cellular Senescence Markers p16INK4a and p21CIP1/WAF Are Predictors of Hodgkin Lymphoma Outcome
Caliò, A., Zamò, A., Ponzoni, M., Zanolin, M. E., Ferreri, A. J. M., Pedron, S., Montagna, L., Parolini, C., Fraifeld, V. E., Wolfson, M., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0508 · Cited by 46
Fisetin and 5‐fluorouracil: Effective combination for PIK3CA‐mutant colorectal cancer
Khan, N., Jajeh, F., Eberhardt, E. L., Miller, D. D., Albrecht, D. M., Doorn, R. R. V., Hruby, M. D., Maresh, M. E., Clipson, L. J., Mukhtar, H., et al. (2019) · International Journal of Cancer · doi:10.1002/ijc.32367 · Cited by 46
Seven-senescence-associated gene signature predicts overall survival for Asian patients with hepatocellular carcinoma
Xiang, X., Yang, L., Zhang, X. Y., Ma, X., Miao, R., Gu, J., Fu, Y., Yao, Q., Zhang, J., Liu, C., et al. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i14.1715 · Cited by 45
Fisetin and polymeric micelles encapsulating fisetin exhibit potent cytotoxic effects towards ovarian cancer cells
Xiao, X., Zou, J., Fang, Y., Meng, Y., Xiao, C., Fu, J., Liu, S., Bai, P., & Yao Zong, Y. U. A. N. (2018) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-018-2127-7 · Cited by 42
Combination with vorinostat overcomes ABT-263 (navitoclax) resistance of small cell lung cancer
Nakajima, W., Sharma, K., Hicks, M. A., Le, N., Brown, R., Krystal, G. W., & Harada, H. (2015) · Cancer Biology & Therapy · doi:10.1080/15384047.2015.1108485 · Cited by 42 · cited 1×
“2016 [97] In vitro Vorinostat+Navitoclax Small cell lung cancer Increased induction of apoptosis with combination”
Background
Navitoclax (ABT‐263) and bendamustine ± rituximab induce enhanced killing of non‐Hodgkin's lymphoma tumours in vivo
Ackler, S., Mitten, M., Chen, J., Clarin, J. D., Foster, K., Jin, S. S., Phillips, D., Schlessinger, S., Wang, B., Leverson, J. D., et al. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02048.x · Cited by 40 · cited 1×
“2012 [98] In vivo mouse model Bendamustine+Navitoclax ±Rituximab Non-Hodgkins lymphoma Enhanced efficacy in combination”
Fisetin, a dietary bioflavonoid, reverses acquired Cisplatin-resistance of lung adenocarcinoma cells through MAPK/Survivin/Caspase pathway.
Zhuo, W., Zhang, L., Zhu, Y. Z., Zhu, B., & Chen, Z. (2015) · Europe PMC (PubMed Central) · Cited by 40
Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with irinotecan: results of an open-label, phase 1 study
Tolcher, A. W., LoRusso, P. M., Arzt, J. A., Busman, T. A., Lian, G., Rudersdorf, N. S., Vanderwal, C. A., Waring, J. F., Yang, J., Holen, K. D., et al. (2015) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-015-2882-9 · Cited by 40 · cited 1×
“2015 [99] Phase 1 clinical trial Irinotecan+Navitoclax Advanced solid tumours, n = 31 6% rate of partial response”
Background
Increased expression of senescence markers p14ARF and p16INK4a in breast cancer is associated with an increased risk of disease recurrence and poor survival outcome
Pare, R., Shin, J., & Lee, C. S. (2016) · Histopathology · doi:10.1111/his.12948 · Cited by 37 · cited 1×
“Another study of breast cancer demonstrated that the increased expressions of senescence markers p14ARF and p16INK4a were associated with increased risk of disease recurrence and poor survival outcomes [43].”
Background
Senescence‐related genes possibly responsible for poor liver regeneration after hepatectomy in elderly patients
Zhu, C., Ikemoto, T., Utsunomiya, T., Yamada, S., Morine, Y., Imura, S., Arakawa, Y., Takasu, C., Ishikawa, D., & Shimada, M. (2013) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.12468 · Cited by 37 · cited 1×
“Few studies have directly assessed the relationship with senescence and surgical outcomes; however, p16 expression is negatively correlated with liver regeneration after hepatectomy in older patients [83] and the molecular aging marker CDKN2A has been shown to predict renal allograft function after 1 year in renal tra…”
Background
Expression of p16 and pRB in invasive breast cancer.
Shin, E., Jung, W. H., & Koo, J. S. (2015) · PubMed · Cited by 37
Biomarkers in the path from cellular senescence to frailty
Zampino, M., Ferrucci, L., & Semba, R. D. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.110750 · Cited by 35 · cited 1×
“Biomarkers of frailty are generally linked to the presence of chronic low grade inflammation [88] and a range of inflammatory markers have been studied and correlate with poor treatment outcomes across a range of diseases [89].”
Background
Frailty and cognitive impairment: Unique challenges in the older emergency surgical patient
Moug, S., Stechman, M., McCarthy, K., Pearce, L. E., Myint, P. K., & Hewitt, J. (2016) · Annals of The Royal College of Surgeons of England · doi:10.1308/rcsann.2016.0087 · Cited by 35 · cited 1×
“Frailty is present in approximately 25% of the older surgical population and is linked to longer hospital stays and higher post-surgical mortality rates [85,86].”
Background
Navitoclax augments the activity of carboplatin and paclitaxel combinations in ovarian cancer cells
Stamelos, V. A., Robinson, E., Redman, C. W. E., & Richardson, A. (2012) · Gynecologic Oncology · doi:10.1016/j.ygyno.2012.11.019 · Cited by 30 · cited 1×
“2013 [95] In vitro Naviticlax+Paclitaxel or Carboplatin Ovarian cancer More than additive cell killing with combination”
Background
The in situ local immune response, tumour senescence and proliferation in colorectal cancer
Roxburgh, C. S. D., Richards, C. H., Macdonald, A. I., Powell, A. G. M. T., McGlynn, L. M., McMillan, D. C., Horgan, P. G., Edwards, J., & Shiels, P. G. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.556 · Cited by 29
Senescence marker protein 30 (SMP30) serves as a potential prognostic indicator in hepatocellular carcinoma
Mo, Z., Zheng, S., Lv, Z., Zhuang, Y., Lan, X., Wang, F., Lü, X., Zhao, Y., & Zhou, S. (2016) · Scientific Reports · doi:10.1038/srep39376 · Cited by 26
‘Stemness’ and ‘senescence’ related escape pathways are dose dependent in lung cancer cells surviving post irradiation
Tsolou, A., Lamprou, I., Fortosi, A.-O., Liousia, M., Giatromanolaki, A. N., & Koukourakis, M. I. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116562 · Cited by 25 · cited 1×
“In irradiated cancer cells, the percentage of senescent cells therefore increases in the remaining “radio-resistant” clones [70].”
Background
Senescent cells: A new Achilles’ heel to exploit for cancer medicine?
Zhang, B., Lam, E. W. ‐., & Sun, Y. (2018) · Aging Cell · doi:10.1111/acel.12875 · Cited by 24 · cited 2×
“Conversely, there is evidence that the secretion of SASP factors may enhance the immune surveillance of tumours and induce bystander cells to become senescent thereby inhibiting tumour progression [66].”
Background
Dynamic Metabolic Response to Adriamycin-Induced Senescence in Breast Cancer Cells
You, R., Dai, J., Zhang, P., Barding, G. A., & Raftery, D. (2018) · Metabolites · doi:10.3390/metabo8040095 · Cited by 24
Differential expression of senescence tumour markers and its implications on survival outcomes of breast cancer patients
Pare, R., Soon, P. S., Shah, A., & Lee, C. S. (2019) · PLOS ONE · doi:10.1371/journal.pone.0214604 · Cited by 23 · cited 1×
“They are also present in cancer and in premalignant lesions and have been evaluated as prognostic markers [41].”
Background
Senescence-associated protein p400 is a prognostic marker in renal cell carcinoma
Macher‐Goeppinger, S., Bermejo, J. L., Schirmacher, P., Pahernik, S. A., Hohenfellner, M., & Roth, W. (2013) · Oncology Reports · doi:10.3892/or.2013.2698 · Cited by 23
Cognitive decline in the middle‐aged after surgery and anaesthesia: results from the Wisconsin Registry for Alzheimer's Prevention cohort
Bratzke, L. C., Koscik, R. L., Schenning, K. J., Clark, L., Sager, M. A., Johnson, S. C., Hermann, B. P., & Hogan, K. J. (2018) · Anaesthesia · doi:10.1111/anae.14216 · Cited by 23 · cited 1×
“Frailty is present in approximately 25% of the older surgical population and is linked to longer hospital stays and higher post-surgical mortality rates [85,86].”
Background
Fisetin inhibits the proliferation of gastric cancer cells and induces apoptosis through suppression of ERK 1/2 activation
Yan, W., Chen, S., Zhao, Y., & Ye, X. (2018) · Oncology Letters · doi:10.3892/ol.2018.8388 · Cited by 19
Combination Treatment with the BRAF V600E Inhibitor Vemurafenib and the BH3 Mimetic Navitoclax for BRAF -Mutant Thyroid Carcinoma
Jeong, J. H., Oh, J. M., Jeong, S. Y., Lee, S., Lee, J., & Ahn, B. (2019) · Thyroid · doi:10.1089/thy.2018.0511 · Cited by 19 · cited 1×
“2019 [96] In vitro Vemurafenib+Navitoclax Papillary thyroid cancer Enhanced growth arrest and increase apoptosis with combination”
Background
Febrile Neutropaenia and Chemotherapy Discontinuation in Women Aged 70 Years or Older Receiving Adjuvant Chemotherapy for Early Breast Cancer
Adjogatse, D., Thanopoulou, E., Okines, A. F. C., Thillai, K., Tasker, F., Johnston, S. R. D., Harper-Wynne, C. L., Torrisi, E., & Ring, A. E. (2014) · Clinical Oncology · doi:10.1016/j.clon.2014.05.002 · Cited by 16 · cited 1×
“Adverse events are also more likely following chemotherapy [87].”
Background

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Aging and aging-related diseases: from molecular mechanisms to interventions and treatments
Guo, J., Huang, X., Dou, L., Yan, M., Shen, T., Tang, W., & Li, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01251-0 · Cited by 1,976
“Cancer Inducing cancer cell senescence is one of antitumor method by inhibiting cancer cell proliferation.(664) SASP released by senescent cancer cells recruit immune cells and suppress the growth of adjacent tumor cells.”
Exploiting 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
Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy
Prasanna, P. G. S., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., Xi, D., Zheng, G., van Deursen, J., Goronzy, J. J., et al. (2021) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djab064 · Cited by 359
“Senolytics act quickly, within 18 hours, eliminating the SnCs induced by therapy (23) and do so in a hitand-run fashion (26,114).”
BackgroundSelf-citation
Mechanisms of cancer cell death induction by paclitaxel: an updated review
Zhao, S., Tang, Y., Wang, R., & Najafi, M. (2022) · APOPTOSIS · doi:10.1007/s10495-022-01750-z · Cited by 200
The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy
Basu, A. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107943 · Cited by 171

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Authors: Wyld, L., Bellantuono, I., Tchkonia, T., Morgan, J., Turner, O., Foss, F., George, J., Danson, S., & Kirkland, J. L.
Affiliations: University of Sheffield (GB)
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA
Sheffield Teaching Hospitals NHS Foundation Trust (GB)
Mayo Clinic (US)
Corresponding author: Wyld, Lynda
ORCID: Wyld, Lynda
Bellantuono, Ilaria
Morgan, Jenna
George, Jayan
Danson, Sarah
Kirkland, James L.
Venue: Cancers
Publisher: MDPI AG
Published: 2020-07-31
Volume: 12
Issue: 8
Pages: 2134
ISSN: 2072-6694 (ISSN-L)
DOI: 10.3390/cancers12082134
PMC: PMC7464619
OpenAlex: W3046779484
Semantic Scholar: 010a7d02a72c6c678a15cb839c87ff57292b93d4
Cited by: 235
References: 125
Citations by year: 2026: 21 · 2025: 35 · 2024: 42 · 2023: 44 · 2022: 57 · 2021: 29 · 2020: 7
FWCI: 4.37
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Cancers (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institute for Health and Care Research (CL-2018-04-002)
National Institute on Aging (P01AG062413)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords: cellular senescence, senotherapy, senolytics, cancer therapy resistance, tumor suppression, telomere shortening, DNA damage, oncogene activation, tumor recurrence, quercetin, navitoclax, fisetin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

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Claims other papers make about this one

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About these checks