Accumulation of senescent cells in tissues with advancing age participates in the pathogenesis of several human age-associated diseases. Specific senescent secretome, the resistance of senescent cells to apoptotic stimuli, and lack of immune system response contribute to the accumulation of senescent cells and their adverse effects in tissues. Inhibition of antiapoptotic machinery, augmented in senescent cells, by BCL-2 protein family inhibitors represents a promising approach to eliminate senescent cells from tissues. This study aimed to explore synergistic and selective senolytic effects of anti-apoptotic BCL-2 family targeting compounds, particularly BH3 mimetics. Using human non-transformed cells RPE-1, BJ, and MRC-5 brought to ionizing radiation-, oncogene-, drug-induced and replicative senescence, we found synergy in combining MCL-1 selective inhibitors with other BH3 mimetics. In an attempt to uncover the mechanism of such synergy, we revealed that the surviving subpopulation of cells resistant to individually applied ABT-737/ABT-263, MIK665, ABT-199, and S63845 BCL-2 family inhibitors showed elevated MCL-1 compared to untreated control cells indicating the presence of a subset of cells expressing high MCL-1 levels and, therefore, resistant to BCL-2 inhibitors within the original population of senescent cells. Overall, we found that combining BCL-2 inhibitors can be beneficial for eliminating senescent cells, thereby enabling use of lower, potentially less toxic, doses of drugs compared to monotherapy, thereby overcoming the resistance of the subpopulation of senescent cells to monotherapy.

Biocev Institute of Biotechnology of the Czech Academy of Sciences Prague Czech Republic

CZ OPENSCREEN Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Genome Integrity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Genome Integrity Unit Danish Cancer Society Research Center Copenhagen Denmark

Zobrazit více v PubMed

Myrianthopoulos V, Evangelou K, Vasileiou PV, Cooks T, Vassilakopoulos TP, Pangalis GA, Kouloukoussa M, Kittas C, Georgakilas AG, Gorgoulis VG. Senescence and senotherapeutics: a new field in cancer therapy. Pharmacol Ther. 2019; 193:31–49. 10.1016/j.pharmthera.2018.08.006 PubMed DOI

Coppé JP, Kauser K, Campisi J, Beauséjour CM. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem. 2006; 281:29568–74. 10.1074/jbc.M603307200 PubMed DOI

Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008; 6:2853–68. 10.1371/journal.pbio.0060301 PubMed DOI PMC

Basisty N, Kale A, Jeon OH, Kuehnemann C, Payne T, Rao C, Holtz A, Shah S, Sharma V, Ferrucci L, Campisi J, Schilling B. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 2020; 18:e3000599. 10.1371/journal.pbio.3000599 PubMed DOI PMC

Nelson G, Wordsworth J, Wang C, Jurk D, Lawless C, Martin-Ruiz C, von Zglinicki T. A senescent cell bystander effect: senescence-induced senescence. Aging Cell. 2012; 11:345–9. 10.1111/j.1474-9726.2012.00795.x PubMed DOI PMC

Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007; 445:656–60. 10.1038/nature05529 PubMed DOI PMC

Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014; 31:722–33. 10.1016/j.devcel.2014.11.012 PubMed DOI PMC

Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, Jansen-Dürr P, Wlaschek M. p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell. 2006; 5:379–89. 10.1111/j.1474-9726.2006.00231.x PubMed DOI

Pereira BI, Devine OP, Vukmanovic-Stejic M, Chambers ES, Subramanian P, Patel N, Virasami A, Sebire NJ, Kinsler V, Valdovinos A, LeSaux CJ, Passos JF, Antoniou A, et al.. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat Commun. 2019; 10:2387. 10.1038/s41467-019-10335-5 PubMed DOI PMC

Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016; 530:184–9. 10.1038/nature16932 PubMed DOI PMC

Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011; 479:232–6. 10.1038/nature10600 PubMed DOI PMC

Baar MP, Brandt RM, Putavet DA, Klein JD, Derks KW, Bourgeois BR, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, et al.. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. 2017; 169:132–47.e16. 10.1016/j.cell.2017.02.031 PubMed DOI PMC

Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, et al.. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016; 22:78–83. 10.1038/nm.4010 PubMed DOI PMC

Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, Alston S, Academia EC, Kilmarx S, et al.. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017; 7:165–76. 10.1158/2159-8290.CD-16-0241 PubMed DOI PMC

Yosef R, Pilpel N, Papismadov N, Gal H, Ovadya Y, Vadai E, Miller S, Porat Z, Ben-Dor S, Krizhanovsky V. p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling. EMBO J. 2017; 36:2280–95. 10.15252/embj.201695553 PubMed DOI PMC

Wang E. Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res. 1995; 55:2284–92. PubMed

Sagiv A, Biran A, Yon M, Simon J, Lowe SW, Krizhanovsky V. Granule exocytosis mediates immune surveillance of senescent cells. Oncogene. 2013; 32:1971–7. 10.1038/onc.2012.206 PubMed DOI PMC

Sasaki M, Kumazaki T, Takano H, Nishiyama M, Mitsui Y. Senescent cells are resistant to death despite low Bcl-2 level. Mech Ageing Dev. 2001; 122:1695–706. 10.1016/s0047-6374(01)00281-0 PubMed DOI

Salovska B, Kondelova A, Pimkova K, Liblova Z, Pribyl M, Fabrik I, Bartek J, Vajrychova M, Hodny Z. Peroxiredoxin 6 protects irradiated cells from oxidative stress and shapes their senescence-associated cytokine landscape. Redox Biol. 2022; 49:102212. 10.1016/j.redox.2021.102212 PubMed DOI PMC

Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene. 2008; 27:6398–406. 10.1038/onc.2008.307 PubMed DOI

Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003; 22:8590–607. 10.1038/sj.onc.1207102 PubMed DOI

Azmi AS, Wang Z, Philip PA, Mohammad RM, Sarkar FH. Emerging Bcl-2 inhibitors for the treatment of cancer. Expert Opin Emerg Drugs. 2011; 16:59–70. 10.1517/14728214.2010.515210 PubMed DOI PMC

Zeitlin BD, Zeitlin IJ, Nör JE. Expanding circle of inhibition: small-molecule inhibitors of Bcl-2 as anticancer cell and antiangiogenic agents. J Clin Oncol. 2008; 26:4180–8. 10.1200/JCO.2007.15.7693 PubMed DOI PMC

Yosef R, Pilpel N, Tokarsky-Amiel R, Biran A, Ovadya Y, Cohen S, Vadai E, Dassa L, Shahar E, Condiotti R, Ben-Porath I, Krizhanovsky V. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016; 7:11190. 10.1038/ncomms11190 PubMed DOI PMC

Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, Pirtskhalava T, Giorgadze N, Johnson KO, Giles CB, Wren JD, Niedernhofer LJ, Robbins PD, Kirkland JL. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016; 15:428–35. 10.1111/acel.12445 PubMed DOI PMC

Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, et al.. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435:677–81. 10.1038/nature03579 PubMed DOI

Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, et al.. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008; 68:3421–8. 10.1158/0008-5472.CAN-07-5836 PubMed DOI

Vogler M, Walter HS, Dyer MJ. Targeting anti-apoptotic BCL2 family proteins in haematological malignancies - from pathogenesis to treatment. Br J Haematol. 2017; 178:364–79. 10.1111/bjh.14684 PubMed DOI

Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 2017; 16:273–84. 10.1038/nrd.2016.253 PubMed DOI

Knight T, Luedtke D, Edwards H, Taub JW, Ge Y. A delicate balance - The BCL-2 family and its role in apoptosis, oncogenesis, and cancer therapeutics. Biochem Pharmacol. 2019; 162:250–61. 10.1016/j.bcp.2019.01.015 PubMed DOI

Ianevski A, He L, Aittokallio T, Tang J. SynergyFinder: a web application for analyzing drug combination dose-response matrix data. Bioinformatics. 2017; 33:2413–5. 10.1093/bioinformatics/btx162 PubMed DOI PMC

Chen R, Guo L, Chen Y, Jiang Y, Wierda WG, Plunkett W. Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia. Blood. 2011; 117:156–64. 10.1182/blood-2010-01-262808 PubMed DOI PMC

Alvandi F, Kwitkowski VE, Ko CW, Rothmann MD, Ricci S, Saber H, Ghosh D, Brown J, Pfeiler E, Chikhale E, Grillo J, Bullock J, Kane R, et al.. U.S. Food and Drug Administration approval summary: omacetaxine mepesuccinate as treatment for chronic myeloid leukemia. Oncologist. 2014; 19:94–9. 10.1634/theoncologist.2013-0077 PubMed DOI PMC

Cao W, Liu Y, Zhang R, Zhang B, Wang T, Zhu X, Mei L, Chen H, Zhang H, Ming P, Huang L. Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells. Sci Rep. 2015; 5:8477. 10.1038/srep08477 PubMed DOI PMC

Meng H, Yang C, Jin J, Zhou Y, Qian W. Homoharringtonine inhibits the AKT pathway and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Leuk Lymphoma. 2008; 49:1954–62. 10.1080/10428190802320368 PubMed DOI

Wei AH, Roberts AW, Spencer A, Rosenberg AS, Siegel D, Walter RB, Caenepeel S, Hughes P, McIver Z, Mezzi K, Morrow PK, Stein A. Targeting MCL-1 in hematologic malignancies: Rationale and progress. Blood Rev. 2020; 44:100672. 10.1016/j.blre.2020.100672 PubMed DOI PMC

Zhu Y, Doornebal EJ, Pirtskhalava T, Giorgadze N, Wentworth M, Fuhrmann-Stroissnigg H, Niedernhofer LJ, Robbins PD, Tchkonia T, Kirkland JL. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY). 2017; 9:955–63. 10.18632/aging.101202 PubMed DOI PMC

Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013; 75:685–705. 10.1146/annurev-physiol-030212-183653 PubMed DOI PMC

Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011; 192:547–56. 10.1083/jcb.201009094 PubMed DOI PMC

Ohtani N, Takahashi A, Mann DJ, Hara E. Cellular senescence: a double-edged sword in the fight against cancer. Exp Dermatol. 2012. (Suppl 1); 21:1–4. 10.1111/j.1600-0625.2012.01493.x PubMed DOI

Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013; 123:966–72. 10.1172/JCI64098 PubMed DOI PMC

Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev. 2014; 28:99–114. 10.1101/gad.235184.113 PubMed DOI PMC

Sagiv A, Krizhanovsky V. Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology. 2013; 14:617–28. 10.1007/s10522-013-9473-0 PubMed DOI

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. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci USA. 2015; 112:E6301–10. 10.1073/pnas.1515386112 PubMed DOI PMC

Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife. 2015; 4:e12997. 10.7554/eLife.12997 PubMed DOI PMC

Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, Rydkina E, Vujcic S, Balan K, Gitlin I, Leonova K, Polinsky A, Chernova OB, Gudkov AV. Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging (Albany NY). 2016; 8:1294–315. 10.18632/aging.100991 PubMed DOI PMC

Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009; 460:392–5. 10.1038/nature08221 PubMed DOI PMC

Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, Hagler M, Jurk D, Smith LA, Casaclang-Verzosa G, Zhu Y, Schafer MJ, Tchkonia T, et al.. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016; 15:973–7. 10.1111/acel.12458 PubMed DOI PMC

Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, Chu Q, Giaccone G, Khaira D, Ramalingam SS, Ranson MR, Dive C, McKeegan EM, et al.. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res. 2012; 18:3163–9. 10.1158/1078-0432.CCR-11-3090 PubMed DOI PMC

Schoenwaelder SM, Jarman KE, Gardiner EE, Hua M, Qiao J, White MJ, Josefsson EC, Alwis I, Ono A, Willcox A, Andrews RK, Mason KD, Salem HH, et al.. Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets. Blood. 2011; 118:1663–74. 10.1182/blood-2011-04-347849 PubMed DOI

Vogler M, Hamali HA, Sun XM, Bampton ET, Dinsdale D, Snowden RT, Dyer MJ, Goodall AH, Cohen GM. BCL2/BCL-X(L) inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation. Blood. 2011; 117:7145–54. 10.1182/blood-2011-03-344812 PubMed DOI

Besancenot R, Chaligné R, Tonetti C, Pasquier F, Marty C, Lécluse Y, Vainchenker W, Constantinescu SN, Giraudier S. A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation. PLoS Biol. 2010; 8:e1000476. 10.1371/journal.pbio.1000476 PubMed DOI PMC

Wang Y, Chang J, Liu X, Zhang X, Zhang S, Zhang X, Zhou D, Zheng G. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY). 2016; 8:2915–26. 10.18632/aging.101100 PubMed DOI PMC

Ferenac M, Polancec D, Huzak M, Pereira-Smith OM, Rubelj I. Early-senescing human skin fibroblasts do not demonstrate accelerated telomere shortening. J Gerontol A Biol Sci Med Sci. 2005; 60:820–9. 10.1093/gerona/60.7.820 PubMed DOI

Smith JR, Whitney RG. Intraclonal variation in proliferative potential of human diploid fibroblasts: stochastic mechanism for cellular aging. Science. 1980; 207:82–4. 10.1126/science.7350644 PubMed DOI

d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003; 426:194–8. 10.1038/nature02118 PubMed DOI

Blagosklonny MV. Anti-aging: senolytics or gerostatics (unconventional view). Oncotarget. 2021; 12:1821–35. 10.18632/oncotarget.28049 PubMed DOI PMC

Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, et al.. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006; 444:633–7. 10.1038/nature05268 PubMed DOI

Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, Schurra C, Garre’ M, Nuciforo PG, Bensimon A, Maestro R, Pelicci PG, d’Adda di Fagagna F. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444:638–42. 10.1038/nature05327 PubMed DOI

Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005; 436:720–4. 10.1038/nature03890 PubMed DOI

Sager R. Senescence as a mode of tumor suppression. Environ Health Perspect. 1991; 93:59–62. 10.1289/ehp.919359 PubMed DOI PMC

Saleh T, Carpenter VJ. Potential Use of Senolytics for Pharmacological Targeting of Precancerous Lesions. Mol Pharmacol. 2021; 100:580–7. 10.1124/molpharm.121.000361 PubMed DOI

Alspach E, Fu Y, Stewart SA. Senescence and the pro-tumorigenic stroma. Crit Rev Oncog. 2013; 18:549–58. 10.1615/critrevoncog.2014010630 PubMed DOI PMC

Michishita E, Nakabayashi K, Suzuki T, Kaul SC, Ogino H, Fujii M, Mitsui Y, Ayusawa D. 5-Bromodeoxyuridine induces senescence-like phenomena in mammalian cells regardless of cell type or species. J Biochem. 1999; 126:1052–9. 10.1093/oxfordjournals.jbchem.a022549 PubMed DOI

Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019; 18:41–58. 10.1038/nrd.2018.168 PubMed DOI

Gürel G, Blaha G, Moore PB, Steitz TA. U2504 determines the species specificity of the A-site cleft antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosome. J Mol Biol. 2009; 389:146–56. 10.1016/j.jmb.2009.04.005 PubMed DOI PMC

Cang S, Iragavarapu C, Savooji J, Song Y, Liu D. ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J Hematol Oncol. 2015; 8:129. 10.1186/s13045-015-0224-3 PubMed DOI PMC

Chen K, Yang Q, Zha J, Deng M, Zhou Y, Fu G, Bi S, Feng L, Xu-Monette ZY, Chen XL, Fu G, Dai Y, Young KH, Xu B. Preclinical evaluation of a regimen combining chidamide and ABT-199 in acute myeloid leukemia. Cell Death Dis. 2020; 11:778. 10.1038/s41419-020-02972-2 PubMed DOI PMC

Lafontaine J, Cardin GB, Malaquin N, Boisvert JS, Rodier F, Wong P. Senolytic Targeting of Bcl-2 Anti-Apoptotic Family Increases Cell Death in Irradiated Sarcoma Cells. Cancers (Basel). 2021; 13:386. 10.3390/cancers13030386 PubMed DOI PMC

Seyfried F, Stirnweiß FU, Niedermayer A, Enzenmüller S, Hörl RL, Münch V, Köhrer S, Debatin KM, Meyer LH. Synergistic activity of combined inhibition of anti-apoptotic molecules in B-cell precursor ALL. Leukemia. 2022; 36:901–12. 10.1038/s41375-021-01502-z PubMed DOI PMC

Vancurova M, Hanzlikova H, Knoblochova L, Kosla J, Majera D, Mistrik M, Burdova K, Hodny Z, Bartek J. PML nuclear bodies are recruited to persistent DNA damage lesions in an RNF168-53BP1 dependent manner and contribute to DNA repair. DNA Repair (Amst). 2019; 78:114–27. 10.1016/j.dnarep.2019.04.001 PubMed DOI

Sapega O, Mikyšková R, Bieblová J, Mrázková B, Hodný Z, Reiniš M. Distinct phenotypes and ‘bystander’ effects of senescent tumour cells induced by docetaxel or immunomodulatory cytokines. Int J Oncol. 2018; 53:1997–2009. 10.3892/ijo.2018.4553 PubMed DOI PMC

Novakova Z, Hubackova S, Kosar M, Janderova-Rossmeislova L, Dobrovolna J, Vasicova P, Vancurova M, Horejsi Z, Hozak P, Bartek J, Hodny Z. Cytokine expression and signaling in drug-induced cellular senescence. Oncogene. 2010; 29:273–84. 10.1038/onc.2009.318 PubMed DOI

Kosar M, Bartkova J, Hubackova S, Hodny Z, Lukas J, Bartek J. Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a). Cell Cycle. 2011; 10:457–68. 10.4161/cc.10.3.14707 PubMed DOI

Feoktistova M, Geserick P, Leverkus M. Crystal Violet Assay for Determining Viability of Cultured Cells. Cold Spring Harb Protoc. 2016. 10.1101/pdb.prot087379 PubMed DOI

STAT3 inhibitor Stattic and its analogues inhibit STAT3 phosphorylation and modulate cytokine secretion in senescent tumour cells