СЕНОЛІЗ ЯК ІНОВАЦІЙНА СТРАТЕГІЯ СЕЛЕКТИВНОГО ВИДАЛЕННЯ СЕНЕСЦЕНТНИХ КЛІТИН
Частина 1. Можливості застосування сенолітиків у лікуванні онкологічних хворих
DOI:
https://doi.org/10.15407/oncology.2026.03.137Ключові слова:
клітинне старіння, передчасне старіння, старіння клітин, індуковане терапією, сеноліз, сенолітики, протипухлинна терапія, комбінована двоетапна схема, доклінічні дослідження, клінічні даніАнотація
Відповідно до сучасних уявлень, клітинне старіння є не суто природним явищем, а може бути індуковане численними стресовими чинниками. Старіння, природне або індуковане, характеризується стабільною і тривалою зупинкою клітинного циклу, перебудовою метаболічних процесів, секрецією факторів, які впливають на прилеглі клітини або діють системно, та втратою чутливості до мітогенних чи апоптотичних сигналів. Зазначених ознак можуть набувати різні типи клітин, зокрема й пухлинні. Накопичення пухлинних сенесцентних клітин, які вижили після проведення протипухлинної терапії, може сприяти розвитку лікарської резистентності, хронічного запалення, формуванню нових кровоносних судин для живлення новоутворення, пригніченню протипухлинної імунної відповіді та утворенню метастатичних вогнищ. З метою подолання небажаних ефектів пухлинних сенесцентних клітин запропоновано новий терапевтичний підхід, заснований на вибірковому знищенні таких клітин, відомий як сеноліз. Метою цієї роботи було критично проаналізувати сучасні дані щодо типів клітинного старіння, механізмів їх формування та основних біомаркерів клітин, що старіють. В огляді також розглядаються особливості сенолізу пухлинних клітин та обговорюються можливості клінічного використання сенолітиків у комбінованій терапії онкологічних хворих.
Посилання
Bautmans I, Knoop V, Amuthavalli Thiyagarajan J, et al. WHO Working Group on Vitality Capacity. WHO working definition of vitality capacity for healthy longevity monitoring. Lancet Healthy Longev 2022; 3 (11): e789–e796. https://doi.org/10.1016/S2666-7568(22)00200-8.
Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961; 25: 585–621. https://doi.org/10.1016/0014-4827(61)90192-6.
Serrano M, Lin AW, McCurrach ME, et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88 (5): 593–602. https://doi.org/10.1016/s0092-8674(00)81902-9.
Chang BD, Broude EV, Dokmanovic M, et al. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res 1999; 59 (15): 3761–7. PMID: 10446993.
Jones KR, Elmore LW, Jackson-Cook C, et al. p53-Dependent accelerated senescence induced by ionizing radiation in breast tumour cells. Int J Radiat Biol 2005; 81 (6): 445–8. https://doi.org/10.1080/09553000500168549.
d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003; 426 (6963): 194–8. https://doi.org/10.1038/nature02118.
Duan J, Duan J, Zhang Z, et al. Irreversible cellular senescence induced by prolonged exposure to H2O2 involves DNA-damage-and-repair genes and telomere shortening. Int J Biochem Cell Biol 2005; 37 (7): 1407–20. https://doi.org/10.1016/j.biocel.2005.01.010.
Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 2018; 25 (3): 486–541. https://doi.org/10.1038/s41418-017-0012-4.
Gorgoulis V, Adams PD, Alimonti A, et al. Cellular senescence: Defining a path forward. Cell 2019; 179 (4): 813–27. https://doi.org/10.1016/j.cell.2019.10.005.
González-Gualda E, Baker AG, Fruk L, et al. A guide to assessing cellular senescence in vitro and in vivo. FEBS J 2021; 288 (1): 56–80. https://doi.org/10.1111/febs.15570.
Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer. Nat Rev Cancer 2022; 22 (6): 340–55. https://doi.org/10.1038/s41568-022-00450-9.
Coppé JP, Desprez PY, Krtolica A, et al. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu Rev Pathol 2010; 5: 99–118. https://doi.org/10.1146/annurev-pathol-121808-102144.
Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011; 479 (7372): 232–6. https://doi.org/10.1038/nature10600.
Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles' heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell 2015; 14 (4): 644–58. https://doi.org/10.1111/acel.12344.
Fuhrmann-Stroissnigg H, Ling YY, Zhao J, et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun 2017; 8 (1): 422. https://doi.org/10.1038/s41467-017-00314-z.
Gire V, Roux P, Wynford-Thomas D, et al. DNA damage checkpoint kinase Chk2 triggers replicative senescence. EMBO J 2004; 23 (13): 2554–63. https://doi.org/10.1038/sj.emboj.7600259.
Di Micco R, Fumagalli M, Cicalese A, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 2006; 444 (7119): 638–42. https://doi.org/10.1038/nature05327.
Gorgoulis VG, Halazonetis TD. Oncogene-induced senescence: The bright and dark side of the response. Curr Opin Cell Biol 2010; 22 (6): 816–27. https://doi.org/10.1016/j.ceb.2010.07.013.
Alimonti A, Nardella C, Chen Z, et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J Clin Invest 2010; 120 (3): 681–93. https://doi.org/10.1172/JCI40535.
Lin C, Hadfield MJ, Rathore A, et al. Cellular senescence: A novel mechanism of therapeutic resistance in prostate cancer. Cancer Treat Rev 2026; 142: 103061. https://doi.org/10.1016/j.ctrv.2025.103061.
Federica G, Michela C, Giovanna D. Targeting the DNA damage response in cancer. MedComm (2020) 2024; 5 (11): e788. https://doi.org/10.1002/mco2.788.
Miller WC, Wallace S, Kamm W, et al. Cellular senescence in acute human infectious disease: A systematic review. Front Aging 2024; 5: 1500741. https://doi.org/10.3389/fragi.2024.1500741.
Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 1995; 92 (20): 9363–7. https://doi.org/10.1073/pnas.92.20.9363.
Gagliardi A, Migliari S, Guercio A, et al. Emerging radioligands as tools to track multi-organ senescence. Diagnostics (Basel) 2025; 15 (19): 2518. https://doi.org/10.3390/diagnostics15192518.
Wang Y, Liu J, Ma X, et al. Real-time imaging of senescence in tumors with DNA damage. Sci Rep 2019; 9 (1): 2102. https://doi.org/10.1038/s41598-019-38511-z.
Rodier F, Muñoz DP, Teachenor R, et al. DNA-SCARS: Distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J Cell Sci 2011; 124 (Pt 1): 68–81. https://doi.org/10.1242/jcs.071340.
Freund A, Laberge RM, Demaria M, et al. Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell 2012; 23 (11): 2066–75. https://doi.org/10.1091/mbc.E11-10-0884.
Wang B, Han J, Elisseeff JH, et al. The senescence-associated secretory phenotype and its physiological and pathological implications. Nat Rev Mol Cell Biol 2024; 25 (12): 958–78. https://doi.org/10.1038/s41580-024-00727-x.
Michaloglou C, Vredeveld L, Soengas M et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005; 436 (7051): 720–4. https://doi.org/10.1038/nature03890.
Chen Z, Trotman L, Shaffer D et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005; 436 (7051): 725–30. https://doi.org/10.1038/nature03918.
Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007; 445 (7128): 656–60. https://doi.org/10.1038/nature05529.
Sturmlechner I, Zhang C, Sine CC, et al. p21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science 2021; 374 (6567): eabb3420. https://doi.org/10.1126/science.abb3420.
Chen HA, Ho YJ, Mezzadra R, et al. Senescence rewires microenvironment sensing to facilitate antitumor immunity. Cancer Discov 2023; 13 (2): 432–53. https://doi.org/10.1158/2159-8290.CD-22-0528.
Criscione SW, De Cecco M, Siranosian B, et al. Reorganization of chromosome architecture in replicative cellular senescence. Sci Adv 2016; 2 (2): e1500882. https://doi.org/10.1126/sciadv.1500882.
De Cecco M, Criscione SW, Peckham EJ, et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 2013; 12 (2): 247–56. https://doi.org/10.1111/acel.12047.
Krtolica A, Parrinello S, Lockett S, et al. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging. Proc Natl Acad Sci U S A 2001; 98 (21): 12072–7. https://doi.org/10.1073/pnas.211053698.
Bavik C, Coleman I, Dean JP, et al. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res 2006; 66 (2): 794–802. https://doi.org/10.1158/0008-5472.CAN-05-1716.
Parrinello S, Coppe JP, Krtolica A, et al. Stromal-epithelial interactions in aging and cancer: Senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 2005; 118 (Pt 3): 485–96. https://doi.org/10.1242/jcs.01635.
Ohanna M, Cheli Y, Bonet C, et al. Secretome from senescent melanoma engages the STAT3 pathway to favor reprogramming of naive melanoma towards a tumor-initiating cell phenotype. Oncotarget 2013; 4 (12): 2212–24. https://doi.org/10.18632/oncotarget.1143.
Kim YH, Choi YW, Lee J, et al. Senescent tumor cells lead the collective invasion in thyroid cancer. Nat Commun 2017; 8: 15208. https://doi.org/10.1038/ncomms15208.
Coppé JP, Kauser K, Campisi J, et al. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem 2006; 281 (40): 29568–74. https://doi.org/10.1074/jbc.M603307200.
Eyman D, Damodarasamy M, Plymate SR, et al. CCL5 secreted by senescent aged fibroblasts induces proliferation of prostate epithelial cells and expression of genes that modulate angiogenesis. J Cell Physiol 2009; 220 (2): 376–81. https://doi.org/10.1002/jcp.21776.
Ruhland MK, Loza AJ, Capietto AH, et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat Commun 2016; 7: 11762. https://doi.org/10.1038/ncomms11762.
Chang J, Wang Y, Shao L, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 2016; 22 (1): 78–83. https://doi.org/10.1038/nm.4010.
Philchenkov AA, Zavelevich MP, Blokhin DY. The combining effect of ionizing radiation and quercetin on human leukemic cells. Clin Oncol (Kyiv) 2011; (2): 225–6 (in Russian).
Baar MP, Brandt RMC, Putavet DA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 2017; 169 (1): 132–47.e16. https://doi.org/10.1016/j.cell.2017.02.031.
Beltzig L, Christmann M, Kaina B. Abrogation of cellular senescence induced by temozolomide in glioblastoma cells: Search for senolytics. Cells 2022; 11 (16): 2588. https://doi.org/10.3390/cells11162588.
Luffman N, Hu B, Koblinski J, et al. Sacituzumab Govitecan as an effective strategy for sensitizing chemoresistant HNSCC cells to senolytic intervention. bioRxiv [Preprint] 2026: 2026.04.13.718209. https://doi.org/10.64898/2026.04.13.718209.
Wang L, Leite de Oliveira R, Wang C, et al. High-throughput functional genetic and compound screens identify targets for senescence induction in cancer. Cell Rep 2017; 21 (3): 773–83. https://doi.org/10.1016/j.celrep.2017.09.085.
Niklasson M, Dalmo E, Segerman A, et al. p21-dependent senescence induction by BMP4 renders glioblastoma cells vulnerable to senolytics. Int J Mol Sci 2025; 26 (9): 3974. https://doi.org/10.3390/ijms26093974.
Vardon A, Haston S, Hamdi H, et al. Navitoclax acts synergistically with irradiation to induce apoptosis in preclinical models of H3K27M-altered diffuse midline glioma. Sci Rep 2025; 15 (1): 45094. https://doi.org/10.1038/s41598-025-32676-6.
Softah A, Alotaibi MR, Alhoshani AR, et al. The combination of radiation with PARP inhibition enhances senescence and sensitivity to the senolytic, navitoclax, in triple negative breast tumor cells. Biomedicines 2023; 11 (11): 3066. https://doi.org/10.3390/biomedicines11113066.
Alcon C, Kovatcheva M, Morales-Sánchez P, et al. HRK downregulation and augmented BCL-xL binding to BAK confer apoptotic protection to therapy-induced senescent melanoma cells. Cell Death Differ 2025; 32 (4): 646–56. https://doi.org/10.1038/s41418-024-01417-z.
Tsuji K, Kida Y, Koshikawa N, et al. Suppression of non-small-cell lung cancer A549 tumor growth by an mtDNA mutation-targeting pyrrole-imidazole polyamide-triphenylphosphonium and a senolytic drug. Cancer Sci 2022; 113 (4): 1321–37. https://doi.org/10.1111/cas.15290.
Troiani M, Colucci M, D'Ambrosio M, et al. Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer. Nat Commun 2022; 13 (1): 2177. https://doi.org/10.1038/s41467-022-29824-1.
Ochiiwa H, Wakasa T, Kataoka Y, et al. IAP antagonists selectively eliminate therapy-induced senescent cancer cells via TNFα-independent apoptosis. Cancer Sci 2026; 117 (4): 1043–56. https://doi.org/10.1111/cas.70329.
Sallbach J, Woods M, Rasenberger B, et al. The cell cycle inhibitor p21CIP1 is essential for irinotecan-induced senescence and plays a decisive role in re-sensitization of temozolomide-resistant glioblastoma cells to irinotecan. Biomed Pharmacother 2024; 181: 117634. https://doi.org/10.1016/j.biopha.2024.117634.
Wang C, Vegna S, Jin H, Benedict B, et al. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature 2019; 574 (7777): 268–72. https://doi.org/10.1038/s41586-019-1607-3.
Samaraweera L, Adomako A, Rodriguez-Gabin A, et al. A novel indication for panobinostat as a senolytic drug in NSCLC and HNSCC. Sci Rep 2017; 7 (1): 1900. https://doi.org/10.1038/s41598-017-01964-1.
Finnegan RM, Elshazly AM, Patel NH, et al. The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer. Front Oncol 2023; 12: 966441. https://doi.org/10.3389/fonc.2022.966441.
Le HH, Cinaroglu SS, Manalo EC, et al. Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells. EBioMedicine 2021; 73: 103646. https://doi.org/10.1016/j.ebiom.2021.103646.
Colucci M, Zumerle S, Bressan S, et al. Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells. Cancer Cell 2024; 42 (4): 646–61.e9. https://doi.org/10.1016/j.ccell.2024.02.004.
Russo M, Moccia S, Luongo D, et al. Senolytic flavonoids enhance type-I and type-II cell death in human radioresistant colon cancer cells through AMPK/MAPK pathway. Cancers (Basel) 2023; 15 (9): 2660. https://doi.org/10.3390/cancers15092660.
Lewińska A, Przybylski P, Adamczyk-Grochala J, et al. Senolysis-based elimination of chemotherapy-induced senescent breast cancer cells by quercetin derivative with blocked hydroxy groups. Cancers (Basel) 2022; 14 (3): 605. https://doi.org/10.3390/cancers14030605.
Chen L, Guo J, Li F, Gao M, et al. FUCA2 Sustains AKT signaling and suppresses senescence by antagonizing FUT3-mediated ErbB3 fucosylation in lung adenocarcinoma. Adv Sci (Weinh) 2026; 13 (44): e23667. https://doi.org/10.1002/advs.202523667.
Wang L, Jin H, Jochems F, et al. cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis. Nat Cancer 2022; 3 (11): 1284–99. https://doi.org/10.1038/s43018-022-00462-2.
González-Gualda E, Pàez-Ribes M, Lozano-Torres B, et al. Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell 2020; 19 (4): e13142. https://doi.org/10.1111/acel.13142.
Philchenkov A, Miura K. The IAP protein family, SMAC mimetics and cancer treatment. Crit Rev Oncog 2016; 21 (3–4):185–202. https://doi.org/10.1615/CritRevOncog.2016017032.
Colville A, Liu JY, Rodriguez-Mateo C, et al. Death-seq identifies regulators of cell death and senolytic therapies. Cell Metab 2023; 35 (10): 1814–29.e6. https://doi.org/10.1016/j.cmet.2023.08.008.
Amor C, Feucht J, Leibold J, et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 2020; 583 (7814): 127–32. https://doi.org/10.1038/s41586-020-2403-9.
Zhang Z, Ho YJ, Fang X, et al. A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR T cell therapy. Cell 2026; 189 (10): 2898–917.e42. https://doi.org/10.1016/j.cell.2026.03.002.
Liu N, Wu J, Deng E, et al. Immunotherapy and senolytics in head and neck squamous cell carcinoma: Phase 2 trial results. Nat Med 2025; 31 (9): 3047–61. https://doi.org/10.1038/s41591-025-03873-7.
Acklin S, Zhang M, Du W, et al. Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice. Sci Rep 2020; 10 (1): 14170. https://doi.org/10.1038/s41598-020-71042-6.
Lérida-Viso A, Fernández AE, Morellá-Aucejo Á, et al. Pharmacological senolysis reduces doxorubicin-induced cardiotoxicity and improves cardiac function in mice. Pharmacol Res 2022; 183: 106356. https://doi.org/10.1016/j.phrs.2022.106356.
Kovacovicova K, Skolnaja M, Heinmaa M, et al. Senolytic cocktail dasatinib+quercetin (D+Q) does not enhance the efficacy of senescence-inducing chemotherapy in liver cancer. Front Oncol 2018; 8: 459. https://doi.org/10.3389/fonc.2018.00459.
Li R, Wei Y, Xiong C, et al. Targeted delivery of liposomal senolytics to alleviate cellular senescence-induced bone loss. Fundam Res 2024; 5 (4): 1429–39. https://doi.org/10.1016/j.fmre.2024.12.010.
Philchenkov A, Dubrovska A. Cancer stem cells as a therapeutic target: Current clinical development and future prospective. Stem Cells 2024; 42 (3): 173–99. https://doi.org/10.1093/stmcls/sxad092.
Short S, Fielder E, Miwa S, et al. Senolytics and senostatics as adjuvant tumour therapy. EBioMedicine 2019; 41: 683–92. https://doi.org/10.1016/j.ebiom.2019.01.056.
Czajkowski K, Herbet M, Murias M, et al. Senolytics: Charting a new course or enhancing existing anti-tumor therapies? Cell Oncol (Dordr) 2025; 48 (2): 351–71. https://doi.org/10.1007/s13402-024-01018-5.
