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Small molecule compounds that induce cellular senescence

Nadezhda V. Petrova, Artem K. Velichko, Sergey V. Razin and 1 more

Aging Cell · 2016 · Review · CC BY

doi:10.1111/acel.12518

Abstract

To date, dozens of stress-induced cellular senescence phenotypes have been reported. These cellular senescence states may differ substantially from each other, as well as from replicative senescence through the presence of specific senescence features. Here, we attempted to catalog virtually all of the cellular senescence-like states that can be induced by low molecular weight compounds. We summarized biological markers, molecular pathways involved in senescence establishment, and specific traits of cellular senescence states induced by more than fifty small molecule compounds.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Cellular senescence is a stable arrest of the cell cycle and is characterized by complex phenotypic changes. It was first described in studies of human fibroblasts that ceased proliferation following an extended cultivation (Hayflick & Moorhead, 1961; Hayflick, 1965). Discovered by Hayflick and Moorhead, senescence in normal human cells was shown to depend on telomere dysfunction originating mainly from replication‐associated telomere shortening (Harley et al., 1990; Allsopp, 1996; Bodnar et al., 1998). This type of senescence is also known as replicative senescence and is the prototypical cellular senescence state. Other forms of senescence (i.e., not linked to proliferation‐dependent telomere shortening) include a variety of prematurely developed cellular senescence phenotypes, similar but not identical to replicative senescence. Many proliferative cell types can undergo so‐called stress‐induced premature senescence (SIPS) upon exposure to subcytotoxic stresses (UV, γ‐irradiation, H2O2, hyperoxia, etc.) (Toussaint et al., 2000, 2002). Oncogene‐induced senescence (OIS) represents another complex senescence phenotype that depends on activation and/or overexpression of oncogenes (Serrano et al., 1997; Bianchi‐Smiraglia & Nikiforov, 2012). The mechanism of OIS involves DNA damage that may be a result of DNA hyper‐replication (Di Micco et al., 2006), replication fork reversal (Neelsen et al., 2013), depletion of nucleotide pools (Mannava et al., 2013), and/or increased levels of reactive oxygen species (ROS) (Lee et al., 1999). Conceptually and mechanistically, OIS is closely related to tumor‐suppressor loss‐induced senescence (Chen et al., 2005; Di Mitri & Alimonti, 2016). Cell‐to‐cell fusion‐induced senescence can also be considered a premature senescence subtype (Chuprin et al., 2013; Burton & Faragher, 2015). The distinctive phenotypic changes typical of various types of cellular senescence are cell enlargement and flattening, senescence‐associated β‐galactosidase activity (SA‐β‐gal), formation of senescence‐associated heterochromatin foci (SAHF), persistent DNA damage response (DDR), and senescence‐associated secretory phenotype (SASP). However, these and several other facultative features of cellular senescence that manifest in each particular case of cell cycle arrest greatly depend on the senescence‐inducing stimulus and the cell type (Campisi, 2013; Salama et al., 2014).

The contribution of cellular senescence to organismal aging is a question of ongoing research (van Deursen, 2014). However, strong evidence for this connection has been reported recently. Specifically, it was shown that clearance of age‐accumulated p16INK4A‐positive senescent cells in mice could extend their healthy lifespan (Baker et al., 2011, 2016). Several chemical compounds that specifically target senescent cells have been identified in the last 2 years (so‐called senolytic drugs) (Xu et al., 2015b; Zhu et al., 2015a,b). It was shown that clearance of senescent cells by such drugs may alleviate age‐related vasomotor dysfunction and frailty, enhance adipogenesis, rejuvenate haematopoietic stem cells after total‐body irradiation, and, generally, extend lifespan (Xu et al., 2015a; Zhu et al., 2015b; Roos et al., 2016). Furthermore, these studies confirm the known pathological impact of cellular senescence, exemplified by cellular dysfunction, impairment of tissue regeneration, detrimental effects on tissue microenvironment, etc. (Burton & Krizhanovsky, 2014). It is evident that along with its detrimental effects, cellular senescence has clearly defined beneficial physiological functions. For instance, it has been shown recently that cellular senescence plays a role in the differentiation of megakaryocytes (Besancenot et al., 2010), the maturation of the placenta (Chuprin et al., 2013), the restriction of fibrosis (Krizhanovsky et al., 2008; Jun & Lau, 2010; Zhu et al., 2013), tissue repair (Demaria et al., 2014), and embryonic development (Nacher et al., 2006; Munoz‐Espin et al., 2013; Storer et al., 2013). The role of cellular senescence in cancer prevention is well documented (Burton & Krizhanovsky, 2014; Munoz‐Espin & Serrano, 2014).

It is generally agreed in the field that the most important features of cellular senescence are SASP and resistance to apoptosis (Munoz‐Espin & Serrano, 2014; Burton & Faragher, 2015). SASP stimulates immune system‐dependent elimination of unwanted precancerous cells or specific embryonic cells that undergo senescence. Notably, cellular senescence may serve as an alternative to apoptosis in embryonic development as well as in cancer prevention (Childs et al., 2014). It has been shown that failure to undergo senescence triggers apoptosis in a compensatory manner to eliminate transient structures during development (Munoz‐Espin et al., 2013; Storer et al., 2013). Therefore, it may be reasonable to consider some of the cellular senescence states (e.g., SIPS), along with apoptosis, autophagy, necrosis, etc., in terms of the cell stress response rather than aging. However, it is unclear whether or not the cellular senescence that is widely implicated in normal aging, chronic diseases, tumor suppression, tumorigenesis, cell differentiation, and embryogenesis represents a single physiological cellular state.

To date, dozens of stress‐induced cellular senescence phenotypes have been reported. These senescence states may differ substantially from each other, as well as from replicative senescence, through the presence of specific senescence features. Additionally, it has been reported that some stress‐induced senescence states can be overcome, thus challenging the dogma that cellular senescence is an irreversible form of growth arrest (Romanov et al., 2001; Beausejour et al., 2003). Such caveats can lead to confusion regarding the terminology of stress‐induced cellular senescence states; it is not clear whether senescence‐like growth arrest (and variations thereof) resembles ‘true’ cellular senescence. The indispensable characteristics of this ‘true’ cellular senescence are also elusive. It can be argued that SASP (arising along with morphological changes and SA‐β‐gal) may be the most important physiologically relevant feature of cellular senescence; however, SASP has not been studied in most cases of stress‐induced senescence. Here, we attempt to catalog virtually all of the cellular senescence‐like states that can be induced by low molecular weight compounds (Table 1). We summarize the biological markers, molecular pathways involved in senescence establishment, and specific traits of cellular senescence states induced by small compounds, as well as the treatment conditions used. In total, we analyzed more than 50 chemical inducers of cellular senescence and senescence‐like states. These chemical compounds can be functionally classified into eight groups: (1) DNA replication stress inducers (aphidicolin, hydroxyurea, thymidine, bromodeoxyuridine, difluorodeoxycytidine, cyclopentenyl cytosine); (2) DNA‐damaging agents, including (2a) DNA topoisomerase inhibitors (doxorubicin, etoposide, daunorubicin, mitoxantrone, camptothecin), (2b) DNA cross‐linkers (cisplatin, mitomycin C, busulfan, cyclophosphamide, diaziquone), and (2c) drugs with complex effects (actinomycin D, bleomycin, temozolomide); (3) epigenetic modifiers that inhibit DNA methyltransferases (5‐aza‐2′‐deoxycytidine), histone deacetylases (sodium butyrate, trichostatin A, MS‐275, SAHA, LBH589, phenylbutyric acid, valproic acid), histone acetyltransferases (curcumin, C646), and histone methyltransferases (BRD4770); (4) inhibitors of telomerase activity (SYUIQ‐5, BMVC4, pyridostatin, compound 115405, perylene and indole derivatives, harmine, BIBR1532, azidothymidine); (5) inhibitors of cyclin‐dependent kinases (palbociclib, roscovitine, ribociclib); (6) activators of p53 (nutlin 3a, FL118); (7) activators of protein kinase C (TPA/PMA, PEP005, PEP008); and (8) reactive oxygen species (ROS) inducers (hydrogen peroxide, tert‐butyl hydroperoxide, phenyl‐2‐pyridyl ketoxime, phenylaminonaphthoquinones, paraquat).

The table highlights the fact that cancer cells can undergo cellular senescence in vitro just as well as their normal nontransformed counterparts. It is apparent that there is no senescence marker or pathway unique to normal or cancer cells. In most cases, increased SA‐β‐gal, morphological changes, and persistent DDR foci were recorded. SAHF were found in only a few cases (aphidicolin, etoposide, palbociclib, and epigenetic modifiers). SASP was also noted only in some cases; however, this is likely because SASP is not commonly analyzed as a senescence biomarker. Apparently, an implicit consensus was established that the demonstration of SA‐β‐gal, morphological changes, and persistent DDR is sufficient to document a cellular senescence‐like state. It is notable that authors designated these phenotypes as a state of premature senescence or senescence‐like cell cycle arrest, regardless of the set of biomarkers observed in each case.

Extremely prolonged drug exposure (from hours to days) was typically required to induce cellular senescence, as is evidenced by the table. In marginal situations, as in the case of aphidicolin‐induced cell cycle arrest, the full set of senescence biomarkers (SA‐β‐gal, cell enlargement, SAHF, and DDR foci) was maintained, while the drug was present in the culture medium and lost upon drug removal (Maya‐Mendoza et al., 2014). The requirement for prolonged incubation time was found for all groups of chemical compounds analyzed; however, the mechanism of senescence development appeared to differ among these groups. Whereas replication stress inducers, different DNA‐damaging agents, and telomerase inhibitors likely generate a persistent DDR following prolonged introduction of a small number of DNA lesions or telomere uncapping, long‐term incubation with epigenetic modifiers likely causes transcriptional activation of repressed loci (particularly INK4A, which encodes p16 CDK inhibitor). This hypothesis is supported by the fact that, in contrast to DNA damage‐induced cellular senescence, which depends on p21 CDK inhibitor, epigenetically induced senescence is mostly dependent on p16. This characterizes epigenetically induced senescence as ‘causeless’—epigenetic modifiers directly activate molecular pathways maintaining the cellular senescence state without generating any cell stress. In this regard, senescence induced by epigenetic modifiers can resemble developmentally programmed or organismal aging‐associated cellular senescence, while replication stress‐ and DNA damage‐induced senescence are examples of stress‐induced premature senescence states.

It follows from the table that replication stress‐ and DNA damage‐induced cellular senescence mostly depend on the p53‐p21 pathway. The same is basically true for cellular senescence induced by physical stressors such as ionizing radiation (IR) and ultraviolet (UV) (Latonen et al., 2001; Suzuki et al., 2006). It is well known that IR as well as UV can stimulate senescence in a variety of normal and cancer cell lines (Chainiaux et al., 2002; Meng et al., 2003; Jones et al., 2005; Jee et al., 2009). Mechanistically, this type of cellular senescence mostly depends on DNA damage induced by these stressors; this links IR and UV to chemical DNA‐damaging agents. Moreover, IR and UV, along with most of the DNA‐damaging agents presented in the table, induce apoptosis rather than senescence when used at higher doses. These observations further emphasize the relationship between apoptosis and senescence. Accordingly, these cell stress response pathways may operate either as alternatives or as supplement to each other. While prominent (but short term) DNA damage induces apoptosis, prolonged mild DNA damage activates cellular senescence. The p53 transcription factor emerges as a master regulator controlling these cell fate decisions (Purvis et al., 2012).

Funding

This work was supported by a Russian Science Foundation [grant number 14‐24‐00022].

Conflict of interest

None declared.

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    Not in our library10.1111/j.1476-5381.2012.01997.x

  61. 61.

    Ido Y, Duranton A, Lan F, Cacicedo JM, Chen TC, Breton L, Ruderman NB (2012 ) Acute activation of AMP‐activated protein kinase prevents H2O2‐induced premature senescence in primary human keratinocytes. PLoS ONE 7, e35092.

    Not in our library10.1371/journal.pone.0035092

  62. 62.

    Jackson JG, Pant V, Li Q, Chang LL, Quintas‐Cardama A, Garza D, Tavana O, Yang P, Manshouri T, Li Y, El‐Naggar AK, Lozano G (2012 ) p53‐mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell 21, 793–806.

    Not in our library10.1016/j.ccr.2012.04.027

  63. 63.

    Jee HJ, Kim HJ, Kim AJ, Bae YS, Bae SS, Yun J (2009 ) UV light induces premature senescence in Akt1‐null mouse embryonic fibroblasts by increasing intracellular levels of ROS. Biochem. Biophys. Res. Commun. 383, 358–362.

    Not in our library10.1016/j.bbrc.2009.04.017

  64. 64.

    Ji HJ, Rha SY, Jeung HC, Yang SH, An SW, Chung HC (2005 ) Cyclic induction of senescence with intermittent AZT treatment accelerates both apoptosis and telomere loss. Breast Cancer Res. Treat. 93, 227–236.

    Not in our library10.1007/s10549-005-5156-0

  65. 65.

    Joguchi A, Fujii M, Ayusawa D (2004 ) Increased catalase activity in mouse cell mutants resistant to paraquat. Biogerontology 5, 193–200.

    Not in our library10.1023/b:bgen.0000031157.12946.e3

  66. 66.

    Jones KR, Elmore LW, Jackson‐Cook C, Demasters G, Povirk LF, Holt SE, Gewirtz DA (2005 ) p53‐Dependent accelerated senescence induced by ionizing radiation in breast tumour cells. Int. J. Radiat. Biol. 81, 445–458.

    Not in our library10.1080/09553000500168549

  67. 67.

    Jun JI, Lau LF (2010 ) The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 12, 676–685.

    Not in our library10.1038/ncb2070

  68. 68.

    Kim HD, Jang CY, Choe JM, Sohn J, Kim J (2012 ) Phenylbutyric acid induces the cellular senescence through an Akt/p21(WAF1) signaling pathway. Biochem. Biophys. Res. Commun. 422, 213–218.

    Not in our library10.1016/j.bbrc.2012.04.086

  69. 69.

    Kobayashi Y, Lee SS, Arai R, Miki K, Fujii M, Ayusawa D (2012 ) ERK1/2 mediates unbalanced growth leading to senescence induced by excess thymidine in human cells. Biochem. Biophys. Res. Commun. 425, 897–901.

    Not in our library10.1016/j.bbrc.2012.08.006

  70. 70.

    Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW (2008 ) Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667.

    Not in our library10.1016/j.cell.2008.06.049

  71. 71.

    Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, Erusalimsky JD (2004 ) Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J. Cell Sci. 117, 2417–2426.

    Not in our library10.1242/jcs.01097

  72. 72.

    Latonen L, Taya Y, Laiho M (2001 ) UV‐radiation induces dose‐dependent regulation of p53 response and modulates p53‐HDM2 interaction in human fibroblasts. Oncogene 20, 6784–6793.

    Not in our library10.1038/sj.onc.1204883

  73. 73.

    Lee AC, Fenster BE, Ito H, Takeda K, Bae NS, Hirai T, Yu ZX, Ferrans VJ, Howard BH, Finkel T (1999 ) Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J. Biol. Chem. 274, 7936–7940.

    Not in our library10.1074/jbc.274.12.7936

  74. 74.

    Leontieva OV, Blagosklonny MV (2013 ) CDK4/6‐inhibiting drug substitutes for p21 and p16 in senescence: duration of cell cycle arrest and MTOR activity determine geroconversion. Cell Cycle 12, 3063–3069.

    Not in our library10.4161/cc.26130

  75. 75.

    Leontieva OV, Gudkov AV, Blagosklonny MV (2010 ) Weak p53 permits senescence during cell cycle arrest. Cell Cycle 9, 4323–4327.

    Not in our library10.4161/cc.9.21.13584

  76. 76.

    Leontieva OV, Demidenko ZN, Blagosklonny MV (2013 ) MEK drives cyclin D1 hyperelevation during geroconversion. Cell Death Differ. 20, 1241–1249.

    Not in our library10.1038/cdd.2013.86

  77. 77.

    Li XN, Shu Q, Su JM, Perlaky L, Blaney SM, Lau CC (2005 ) Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. Mol. Cancer Ther. 4, 1912–1922.

    Not in our library10.1158/1535-7163.mct-05-0184

  78. 78.

    Ling X, Xu C, Fan C, Zhong K, Li F, Wang X (2014 ) FL118 induces p53‐dependent senescence in colorectal cancer cells by promoting degradation of MdmX. Cancer Res. 74, 7487–7497.

    Not in our library10.1158/0008-5472.can-14-0683

  79. 79.

    Linge A, Weinhold K, Blasche R, Kasper M, Barth K (2007 ) Downregulation of caveolin‐1 affects bleomycin‐induced growth arrest and cellular senescence in A549 cells. Int. J. Biochem. Cell Biol. 39, 1964–1974.

    Not in our library10.1016/j.biocel.2007.05.018

  80. 80.

    Litwiniec A, Grzanka A, Helmin‐Basa A, Gackowska L, Grzanka D (2010 ) Features of senescence and cell death induced by doxorubicin in A549 cells: organization and level of selected cytoskeletal proteins. J. Cancer Res. Clin. Oncol. 136, 717–736.

    Not in our library10.1007/s00432-009-0711-4

  81. 81.

    Litwiniec A, Gackowska L, Helmin‐Basa A, Zuryn A, Grzanka A (2013 ) Low‐dose etoposide‐treatment induces endoreplication and cell death accompanied by cytoskeletal alterations in A549 cells: does the response involve senescence? The possible role of vimentin. Cancer Cell Int. 13, 9.

    Not in our library10.1186/1475-2867-13-9

  82. 82.

    Manfe V, Biskup E, Johansen P, Kamstrup MR, Krejsgaard TF, Morling N, Wulf HC, Gniadecki R (2012 ) MDM2 inhibitor nutlin‐3a induces apoptosis and senescence in cutaneous T‐cell lymphoma: role of p53. J. Invest. Dermatol. 132, 1487–1496.

    Not in our library10.1038/jid.2012.10

  83. 83.

    Mannava S, Moparthy KC, Wheeler LJ, Natarajan V, Zucker SN, Fink EE, Im M, Flanagan S, Burhans WC, Zeitouni NC, Shewach DS, Mathews CK, Nikiforov MA (2013 ) Depletion of deoxyribonucleotide pools is an endogenous source of DNA damage in cells undergoing oncogene‐induced senescence. Am. J. Pathol. 182, 142–151.

    Not in our library10.1016/j.ajpath.2012.09.011

  84. 84.

    Mansilla S, Pina B, Portugal J (2003 ) Daunorubicin‐induced variations in gene transcription: commitment to proliferation arrest, senescence and apoptosis. Biochem. J. 372, 703–711.

    Not in our library10.1042/bj20021950

  85. 85.

    Marconett CN, Sundar SN, Tseng M, Tin AS, Tran KQ, Mahuron KM, Bjeldanes LF, Firestone GL (2011 ) Indole‐3‐carbinol downregulation of telomerase gene expression requires the inhibition of estrogen receptor‐alpha and Sp1 transcription factor interactions within the hTERT promoter and mediates the G1 cell cycle arrest of human breast cancer cells. Carcinogenesis 32, 1315–1323.

    Not in our library10.1093/carcin/bgr116

  86. 86.

    Marusyk A, Wheeler LJ, Mathews CK, DeGregori J (2007 ) p53 mediates senescence‐like arrest induced by chronic replicational stress. Mol. Cell. Biol. 27, 5336–5351.

    Not in our library10.1128/mcb.01316-06

  87. 87.

    Mason SA, Cozzi SJ, Pierce CJ, Pavey SJ, Parsons PG, Boyle GM (2010 ) The induction of senescence‐like growth arrest by protein kinase C‐activating diterpene esters in solid tumor cells. Invest. New Drugs 28, 575–586.

    Not in our library10.1007/s10637-009-9292-y

  88. 88.

    Masterson JC, O'Dea S (2007 ) 5‐Bromo‐2‐deoxyuridine activates DNA damage signalling responses and induces a senescence‐like phenotype in p16‐null lung cancer cells. Anticancer Drugs 18, 1053–1068.

    Not in our library10.1097/cad.0b013e32825209f6

  89. 89.

    Maya‐Mendoza A, Merchut‐Maya JM, Bartkova J, Bartek J, Streuli CH, Jackson DA (2014 ) Immortalised breast epithelia survive prolonged DNA replication stress and return to cycle from a senescent‐like state. Cell Death Dis. 5, e1351.

    Not in our library10.1038/cddis.2014.315

  90. 90.

    McKenna E, Traganos F, Zhao H, Darzynkiewicz Z (2012 ) Persistent DNA damage caused by low levels of mitomycin C induces irreversible cell senescence. Cell Cycle 11, 3132–3140.

    Not in our library10.4161/cc.21506

  91. 91.

    Meng A, Wang Y, Van Zant G, Zhou D (2003 ) Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells. Cancer Res. 63, 5414–5419.

    Not in our library

  92. 92.

    Mhaidat NM, Zhang XD, Allen J, Avery‐Kiejda KA, Scott RJ, Hersey P (2007 ) Temozolomide induces senescence but not apoptosis in human melanoma cells. Br. J. Cancer 97, 1225–1233.

    Not in our library10.1038/sj.bjc.6604017

  93. 93.

    Minieri V, Saviozzi S, Gambarotta G, Lo Iacono M, Accomasso L, Cibrario Rocchietti E, Gallina C, Turinetto V, Giachino C (2015 ) Persistent DNA damage‐induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells. J. Cell Mol. Med. 19, 734–743.

    Not in our library10.1111/jcmm.12387

  94. 94.

    Modrak DE, Leon E, Goldenberg DM, Gold DV (2009 ) Ceramide regulates gemcitabine‐induced senescence and apoptosis in human pancreatic cancer cell lines. Mol. Cancer Res. 7, 890–896.

    Not in our library10.1158/1541-7786.mcr-08-0457

  95. 95.

    Mosieniak G, Adamowicz M, Alster O, Jaskowiak H, Szczepankiewicz AA, Wilczynski GM, Ciechomska IA, Sikora E (2012 ) Curcumin induces permanent growth arrest of human colon cancer cells: link between senescence and autophagy. Mech. Ageing Dev. 133, 444–455.

    Not in our library10.1016/j.mad.2012.05.004

  96. 96.

    Muller S, Sanders DA, Di Antonio M, Matsis S, Riou JF, Rodriguez R, Balasubramanian S (2012 ) Pyridostatin analogues promote telomere dysfunction and long‐term growth inhibition in human cancer cells. Org. Biomol. Chem. 10, 6537–6546.

    Not in our library10.1039/c2ob25830g

  97. 97.

    Munoz‐Espin D, Serrano M (2014 ) Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496.

    Not in our library10.1038/nrm3823

  98. 98.

    Munoz‐Espin D, Canamero M, Maraver A, Gomez‐Lopez G, Contreras J, Murillo‐Cuesta S, Rodriguez‐Baeza A, Varela‐Nieto I, Ruberte J, Collado M, Serrano M (2013 ) Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118.

    Not in our library10.1016/j.cell.2013.10.019

  99. 99.

    Nacher V, Carretero A, Navarro M, Armengol C, Llombart C, Rodriguez A, Herrero‐Fresneda I, Ayuso E, Ruberte J (2006 ) The quail mesonephros: a new model for renal senescence? J. Vasc. Res. 43, 581–586.

    Not in our library10.1159/000096076

  100. 100.

    Nair RR, Bagheri M, Saini DK (2015 ) Temporally distinct roles of ATM and ROS in genotoxic‐stress‐dependent induction and maintenance of cellular senescence. J. Cell Sci. 128, 342–353.

    Not in our library10.1242/jcs.159517

  101. 101.

    Neelsen KJ, Zanini IM, Herrador R, Lopes M (2013 ) Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates. J. Cell Biol. 200, 699–708.

    Not in our library10.1083/jcb.201212058

  102. 102.

    Ogryzko VV, Hirai TH, Russanova VR, Barbie DA, Howard BH (1996 ) Human fibroblast commitment to a senescence‐like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol. Cell. Biol. 16, 5210–5218.

    Not in our library10.1128/mcb.16.9.5210

  103. 103.

    Oliva JL, Caino MC, Senderowicz AM, Kazanietz MG (2008 ) S‐Phase‐specific activation of PKC alpha induces senescence in non‐small cell lung cancer cells. J. Biol. Chem. 283, 5466–5476.

    Not in our library10.1074/jbc.m707576200

  104. 104.

    Ota H, Eto M, Kano MR, Ogawa S, Iijima K, Akishita M, Ouchi Y (2008 ) Cilostazol inhibits oxidative stress‐induced premature senescence via upregulation of Sirt1 in human endothelial cells. Arterioscler. Thromb. Vasc. Biol. 28, 1634–1639.

    Not in our library10.1161/atvbaha.108.164368

  105. 105.

    Palaniyappan A (2009 ) Cyclophosphamide induces premature senescence in normal human fibroblasts by activating MAP kinases. Biogerontology 10, 677–682.

    Not in our library10.1007/s10522-009-9215-5

  106. 106.

    Park JI, Jeong JS, Han JY, Kim DI, Gao YH, Park SC, Rodgers GP, Kim IH (2000 ) Hydroxyurea induces a senescence‐like change of K562 human erythroleukemia cell. J. Cancer Res. Clin. Oncol. 126, 455–460.

    Not in our library

  107. 107.

    Park C, Lee I, Kang WK (2006 ) E2F‐1 is a critical modulator of cellular senescence in human cancer. Int. J. Mol. Med. 17, 715–720.

    Not in our library

  108. 108.

    Park JY, Park SH, Weiss RH (2009 ) Disparate effects of roscovitine on renal tubular epithelial cell apoptosis and senescence: implications for autosomal dominant polycystic kidney disease. Am. J. Nephrol. 29, 509–515.

    Not in our library10.1159/000184590

  109. 109.

    Pascal T, Debacq‐Chainiaux F, Boilan E, Ninane N, Raes M, Toussaint O (2007 ) Heme oxygenase‐1 and interleukin‐11 are overexpressed in stress‐induced premature senescence of human WI‐38 fibroblasts induced by tert‐butylhydroperoxide and ethanol. Biogerontology 8, 409–422.

    Not in our library10.1007/s10522-007-9084-8

  110. 110.

    Pazolli E, Alspach E, Milczarek A, Prior J, Piwnica‐Worms D, Stewart SA (2012 ) Chromatin remodeling underlies the senescence‐associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression. Cancer Res. 72, 2251–2261.

    Not in our library10.1158/0008-5472.can-11-3386

  111. 111.

    Perez M, Munoz‐Galvan S, Jimenez‐Garcia MP, Marin JJ, Carnero A (2015 ) Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA. Oncotarget 6, 40557–40574.

    Not in our library10.18632/oncotarget.5829

  112. 112.

    Piegari E, De Angelis A, Cappetta D, Russo R, Esposito G, Costantino S, Graiani G, Frati C, Prezioso L, Berrino L, Urbanek K, Quaini F, Rossi F (2013 ) Doxorubicin induces senescence and impairs function of human cardiac progenitor cells. Basic Res. Cardiol. 108, 334.

    Not in our library10.1007/s00395-013-0334-4

  113. 113.

    Place RF, Noonan EJ, Giardina C (2005 ) HDACs and the senescent phenotype of WI‐38 cells. BMC Cell Biol. 6, 37.

    Not in our library10.1186/1471-2121-6-37

  114. 114.

    te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP (2002 ) DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 62, 1876–1883.

    Not in our library

  115. 115.

    Pospelova TV, Demidenko ZN, Bukreeva EI, Pospelov VA, Gudkov AV, Blagosklonny MV (2009 ) Pseudo‐DNA damage response in senescent cells. Cell Cycle 8, 4112–4118.

    Not in our library10.4161/cc.8.24.10215

  116. 116.

    Prieur A, Besnard E, Babled A, Lemaitre JM (2011 ) p53 and p16(INK4A) independent induction of senescence by chromatin‐dependent alteration of S‐phase progression. Nat. Commun. 2, 473.

    Not in our library10.1038/ncomms1473

  117. 117.

    Probin V, Wang Y, Bai A, Zhou D (2006 ) Busulfan selectively induces cellular senescence but not apoptosis in WI38 fibroblasts via a p53‐independent but extracellular signal‐regulated kinase‐p38 mitogen‐activated protein kinase‐dependent mechanism. J. Pharmacol. Exp. Ther. 319, 551–560.

    Not in our library10.1124/jpet.106.107771

  118. 118.

    Probin V, Wang Y, Zhou D (2007 ) Busulfan‐induced senescence is dependent on ROS production upstream of the MAPK pathway. Free Radic. Biol. Med. 42, 1858–1865.

    Not in our library10.1016/j.freeradbiomed.2007.03.020

  119. 119.

    Purvis JE, Karhohs KW, Mock C, Batchelor E, Loewer A, Lahav G (2012 ) p53 dynamics control cell fate. Science 336, 1440–1444.

    Not in our library10.1126/science.1218351

  120. 120.

    Qu K, Lin T, Wang Z, Liu S, Chang H, Xu X, Meng F, Zhou L, Wei J, Tai M, Dong Y, Liu C (2014 ) Reactive oxygen species generation is essential for cisplatin‐induced accelerated senescence in hepatocellular carcinoma. Front. Med. 8, 227–235.

    Not in our library10.1007/s11684-014-0327-1

  121. 121.

    Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S, Parasuraman S, Caponigro G, Schnepp RW, Wood AC, Pawel B, Cole KA, Maris JM (2013 ) Dual CDK4/CDK6 inhibition induces cell‐cycle arrest and senescence in neuroblastoma. Clin. Cancer Res. 19, 6173–6182.

    Not in our library10.1158/1078-0432.ccr-13-1675

  122. 122.

    Riou JF, Guittat L, Mailliet P, Laoui A, Renou E, Petitgenet O, Megnin‐Chanet F, Helene C, Mergny JL (2002 ) Cell senescence and telomere shortening induced by a new series of specific G‐quadruplex DNA ligands. Proc. Natl Acad. Sci. USA 99, 2672–2677.

    Not in our library10.1073/pnas.052698099

  123. 123.

    Roberson RS, Kussick SJ, Vallieres E, Chen SY, Wu DY (2005 ) Escape from therapy‐induced accelerated cellular senescence in p53‐null lung cancer cells and in human lung cancers. Cancer Res. 65, 2795–2803.

    Not in our library10.1158/0008-5472.can-04-1270

  124. 124.

    Robles SJ, Adami GR (1998 ) Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. Oncogene 16, 1113–1123.

    Not in our library10.1038/sj.onc.1201862

  125. 125.

    Romanov SR, Kozakiewicz BK, Holst CR, Stampfer MR, Haupt LM, Tlsty TD (2001 ) Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature 409, 633–637.

    Not in our library10.1038/35054579

  126. 126.
    Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice · 2016
    No notice
  127. 127.

    Salama R, Sadaie M, Hoare M, Narita M (2014 ) Cellular senescence and its effector programs. Genes Dev. 28, 99–114.

    Not in our library10.1101/gad.235184.113

  128. 128.

    Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, Lowe SW (2002 ) A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346.

    Not in our library10.1016/s0092-8674(02)00734-1

  129. 129.

    Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997 ) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602.

    Not in our library10.1016/s0092-8674(00)81902-9

  130. 130.

    Shimizu H, Bolati D, Adijiang A, Enomoto A, Nishijima F, Dateki M, Niwa T (2010 ) Senescence and dysfunction of proximal tubular cells are associated with activated p53 expression by indoxyl sulfate. Am. J. Physiol. Cell Physiol. 299, C1110–C1117.

    Not in our library10.1152/ajpcell.00217.2010

  131. 131.

    Shimizu H, Bolati D, Adijiang A, Muteliefu G, Enomoto A, Nishijima F, Dateki M, Niwa T (2011 ) NF‐kappaB plays an important role in indoxyl sulfate‐induced cellular senescence, fibrotic gene expression, and inhibition of proliferation in proximal tubular cells. Am. J. Physiol. Cell Physiol. 301, C1201–C1212.

    Not in our library10.1152/ajpcell.00471.2010

  132. 132.

    Sliwinska MA, Mosieniak G, Wolanin K, Babik A, Piwocka K, Magalska A, Szczepanowska J, Fronk J, Sikora E (2009 ) Induction of senescence with doxorubicin leads to increased genomic instability of HCT116 cells. Mech. Ageing Dev. 130, 24–32.

    Not in our library10.1016/j.mad.2008.04.011

  133. 133.

    Spallarossa P, Altieri P, Aloi C, Garibaldi S, Barisione C, Ghigliotti G, Fugazza G, Barsotti A, Brunelli C (2009 ) Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2. Am. J. Physiol. Heart Circ. Physiol. 297, H2169–H2181.

    Not in our library10.1152/ajpheart.00068.2009

  134. 134.

    Storer M, Mas A, Robert‐Moreno A, Pecoraro M, Ortells MC, Di Giacomo V, Yosef R, Pilpel N, Krizhanovsky V, Sharpe J, Keyes WM (2013 ) Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130.

    Not in our library10.1016/j.cell.2013.10.041

  135. 135.

    Sumikawa E, Matsumoto Y, Sakemura R, Fujii M, Ayusawa D (2005 ) Prolonged unbalanced growth induces cellular senescence markers linked with mechano transduction in normal and tumor cells. Biochem. Biophys. Res. Commun. 335, 558–565.

    Not in our library10.1016/j.bbrc.2005.07.106

  136. 136.

    Suzuki T, Minagawa S, Michishita E, Ogino H, Fujii M, Mitsui Y, Ayusawa D (2001 ) Induction of senescence‐associated genes by 5‐bromodeoxyuridine in HeLa cells. Exp. Gerontol. 36, 465–474.

    Not in our library10.1016/s0531-5565(00)00223-0

  137. 137.

    Suzuki M, Suzuki K, Kodama S, Watanabe M (2006 ) Interstitial chromatin alteration causes persistent p53 activation involved in the radiation‐induced senescence‐like growth arrest. Biochem. Biophys. Res. Commun. 340, 145–150.

    Not in our library10.1016/j.bbrc.2005.11.167

  138. 138.

    Suzuki E, Takahashi M, Oba S, Nishimatsu H (2013 ) Oncogene‐ and oxidative stress‐induced cellular senescence shows distinct expression patterns of proinflammatory cytokines in vascular endothelial cells. ScientificWorldJournal 2013, 754735.

    Not in our library10.1155/2013/754735

  139. 139.

    Taka T, Huang L, Wongnoppavich A, Tam‐Chang SW, Lee TR, Tuntiwechapikul W (2013 ) Telomere shortening and cell senescence induced by perylene derivatives in A549 human lung cancer cells. Bioorg. Med. Chem. 21, 883–890.

    Not in our library10.1016/j.bmc.2012.12.020

  140. 140.

    Terao Y, Nishida J, Horiuchi S, Rong F, Ueoka Y, Matsuda T, Kato H, Furugen Y, Yoshida K, Kato K, Wake N (2001 ) Sodium butyrate induces growth arrest and senescence‐like phenotypes in gynecologic cancer cells. Int. J. Cancer 94, 257–267.

    Not in our library10.1002/ijc.1448

  141. 141.

    Toussaint O, Medrano EE, von Zglinicki T (2000 ) Cellular and molecular mechanisms of stress‐induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. Exp. Gerontol. 35, 927–945.

    Not in our library10.1016/s0531-5565(00)00180-7

  142. 142.

    Toussaint O, Royer V, Salmon M, Remacle J (2002 ) Stress‐induced premature senescence and tissue ageing. Biochem. Pharmacol. 64, 1007–1009.

    Not in our library10.1016/s0006-2952(02)01170-x

  143. 143.

    Veena MS, Wilken R, Zheng JY, Gholkar A, Venkatesan N, Vira D, Ahmed S, Basak SK, Dalgard CL, Ravichandran S, Batra RK, Kasahara N, Elashoff D, Fishbein MC, Whitelegge JP, Torres JZ, Wang MB, Srivatsan ES (2014 ) p16 Protein and gigaxonin are associated with the ubiquitination of NFkappaB in cisplatin‐induced senescence of cancer cells. J. Biol. Chem. 289, 34921–34937.

    Not in our library10.1074/jbc.m114.568543

  144. 144.

    Velichko AK, Petrova NV, Razin SV, Kantidze OL (2015 ) Mechanism of heat stress‐induced cellular senescence elucidates the exclusive vulnerability of early S‐phase cells to mild genotoxic stress. Nucleic Acids Res. 43, 6309–6320.

    Not in our library10.1093/nar/gkv573

  145. 145.

    Venturelli S, Berger A, Weiland T, Essmann F, Waibel M, Nuebling T, Hacker S, Schenk M, Schulze‐Osthoff K, Salih HR, Fulda S, Sipos B, Johnstone RW, Lauer UM, Bitzer M (2013 ) Differential induction of apoptosis and senescence by the DNA methyltransferase inhibitors 5‐azacytidine and 5‐aza‐2′‐deoxycytidine in solid tumor cells. Mol. Cancer Ther. 12, 2226–2236.

    Not in our library10.1158/1535-7163.mct-13-0137

  146. 146.

    Vogt M, Haggblom C, Yeargin J, Christiansen‐Weber T, Haas M (1998 ) Independent induction of senescence by p16INK4a and p21CIP1 in spontaneously immortalized human fibroblasts. Cell Growth Differ. 9, 139–146.

    Not in our library

  147. 147.

    Wang X, Wong SC, Pan J, Tsao SW, Fung KH, Kwong DL, Sham JS, Nicholls JM (1998 ) Evidence of cisplatin‐induced senescent‐like growth arrest in nasopharyngeal carcinoma cells. Cancer Res. 58, 5019–5022.

    Not in our library

  148. 148.

    Widodo N, Deocaris CC, Kaur K, Hasan K, Yaguchi T, Yamasaki K, Sugihara T, Ishii T, Wadhwa R, Kaul SC (2007 ) Stress chaperones, mortalin, and pex19p mediate 5‐aza‐2′ deoxycytidine‐induced senescence of cancer cells by DNA methylation‐independent pathway. J. Gerontol. A Biol. Sci. Med. Sci. 62, 246–255.

    Not in our library10.1093/gerona/62.3.246

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    Xiao H, Hasegawa T, Miyaishi O, Ohkusu K, Isobe K (1997 ) Sodium butyrate induces NIH3T3 cells to senescence‐like state and enhances promoter activity of p21WAF/CIP1 in p53‐independent manner. Biochem. Biophys. Res. Commun. 237, 457–460.

    Not in our library10.1006/bbrc.1997.7158

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    Xu WS, Perez G, Ngo L, Gui CY, Marks PA (2005 ) Induction of polyploidy by histone deacetylase inhibitor: a pathway for antitumor effects. Cancer Res. 65, 7832–7839.

    Not in our library10.1158/0008-5472.can-04-4608

  151. 151.
    Targeting senescent cells enhances adipogenesis and metabolic function in old age · 2015
    No notice
  152. 152.

    Xu M, Tchkonia T, Ding H, Ogrodnik M, Lubbers ER, Pirtskhalava T, White TA, Johnson KO, Stout MB, Mezera V, Giorgadze N, Jensen MD, LeBrasseur NK, Kirkland JL (2015b ) JAK inhibition alleviates the cellular senescence‐associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, E6301–E6310.

    Not in our library10.1073/pnas.1515386112

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    Yang KE, Jang HJ, Hwang IH, Chung YH, Choi JS, Lee TH, Chung YJ, Lee MS, Lee MY, Yeo EJ, Jang IS (2016 ) Phenyl 2‐pyridyl ketoxime induces cellular senescence‐like alterations via nitric oxide production in human diploid fibroblasts. Aging Cell 15, 245–255.

    Not in our library10.1111/acel.12429

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    Yeo EJ, Hwang YC, Kang CM, Kim IH, Kim DI, Parka JS, Choy HE, Park WY, Park SC (2000 ) Senescence‐like changes induced by hydroxyurea in human diploid fibroblasts. Exp. Gerontol. 35, 553–571.

    Not in our library10.1016/s0531-5565(00)00108-x

  155. 155.

    Yoshida A, Lee EK, Diehl JA (2016 ) Induction of therapeutic senescence in vemurafenib‐resistant melanoma by extended Inhibition of CDK4/6. Cancer Res. 76, 2990–3002.

    Not in our library10.1158/0008-5472.can-15-2931

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    Yoshizaki K, Fujiki T, Tsunematsu T, Yamashita M, Udono M, Shirahata S, Katakura Y (2009 ) Pro‐senescent effect of hydrogen peroxide on cancer cells and its possible application to tumor suppression. Biosci. Biotechnol. Biochem. 73, 311–315.

    Not in our library10.1271/bbb.80517

  157. 157.

    Young JJ, Patel A, Rai P (2010 ) Suppression of thioredoxin‐1 induces premature senescence in normal human fibroblasts. Biochem. Biophys. Res. Commun. 392, 363–368.

    Not in our library10.1016/j.bbrc.2010.01.026

  158. 158.

    Yuan Y, Wang Q, Paulk J, Kubicek S, Kemp MM, Adams DJ, Shamji AF, Wagner BK, Schreiber SL (2012 ) A small‐molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chem. Biol. 7, 1152–1157.

    Not in our library10.1021/cb300139y

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    Zdanov S, Debacq‐Chainiaux F, Remacle J, Toussaint O (2006 ) Identification of p38MAPK‐dependent genes with changed transcript abundance in H2O2‐induced premature senescence of IMR‐90 hTERT human fibroblasts. FEBS Lett. 580, 6455–6463.

    Not in our library10.1016/j.febslet.2006.10.064

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    von Zglinicki T, Pilger R, Sitte N (2000 ) Accumulation of single‐strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic. Biol. Med. 28, 64–74.

    Not in our library10.1016/s0891-5849(99)00207-5

  161. 161.

    Zhang JW, Zhang SS, Song JR, Sun K, Zong C, Zhao QD, Liu WT, Li R, Wu MC, Wei LX (2014 ) Autophagy inhibition switches low‐dose camptothecin‐induced premature senescence to apoptosis in human colorectal cancer cells. Biochem. Pharmacol. 90, 265–275.

    Not in our library10.1016/j.bcp.2014.05.009

  162. 162.

    Zhao L, Wink M (2013 ) The beta‐carboline alkaloid harmine inhibits telomerase activity of MCF‐7 cells by down‐regulating hTERT mRNA expression accompanied by an accelerated senescent phenotype. PeerJ 1, e174.

    Not in our library10.7717/peerj.174

  163. 163.

    Zhao W, Lin ZX, Zhang ZQ (2004 ) Cisplatin‐induced premature senescence with concomitant reduction of gap junctions in human fibroblasts. Cell Res. 14, 60–66.

    Not in our library10.1038/sj.cr.7290203

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    Zhao H, Halicka HD, Traganos F, Jorgensen E, Darzynkiewicz Z (2010 ) New biomarkers probing depth of cell senescence assessed by laser scanning cytometry. Cytometry A 77, 999–1007.

    Not in our library10.1002/cyto.a.20983

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    Zhou JM, Zhu XF, Lu YJ, Deng R, Huang ZS, Mei YP, Wang Y, Huang WL, Liu ZC, Gu LQ, Zeng YX (2006 ) Senescence and telomere shortening induced by novel potent G‐quadruplex interactive agents, quindoline derivatives, in human cancer cell lines. Oncogene 25, 503–511.

    Not in our library10.1038/sj.onc.1209067

  166. 166.

    Zhou H, Huang B, Han Y, Jin R, Chen S (2013 ) Probucol inhibits JAK2‐STAT pathway activation and protects human glomerular mesangial cells from tert‐butyl hydroperoxide induced premature senescence. Can. J. Physiol. Pharmacol. 91, 671–679.

    Not in our library10.1139/cjpp-2012-0343

  167. 167.
    Senescent Cardiac Fibroblast Is Critical for Cardiac Fibrosis after Myocardial Infarction · 2013
    No notice
  168. 168.
    Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors · 2016
    No notice
  169. 169.
    The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs · 2015
    No notice

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