Login Register Cart 0
Generic placeholder image

Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Cellular Senescence and Senolytic Agents: Recent Updates on Their Role and Applications

Author(s): Lokesh Chandrakar, Ramesh Ambatwar and Gopal L. Khatik*

Volume 24, Issue 2, 2024

Published on: 30 November, 2023

Page: [157 - 178] Pages: 22

DOI: 10.2174/0115680266273698231107110956

Price: $65

Abstract

Cellular senescence, an eternal condition of cell cycle arrest due to cellular stressors, is a sign of aging. Senescent cells (SCs) build up in tissues as they age, impairing their ability to repair themselves by causing the cell cycle to seize in progenitor cells and producing proinflammatory and the senescence-associated secretory phenotype (SASP) or matrix-degrading molecules. SASP aids in the emergence of several age-related diseases. Genetic studies have shown that removing SCs can delay aging and prolong life. Senolytics are small molecules designed to treat numerous age-related disorders can selectively kill SCs. A detailed discussion on senolytics and their potential as therapeutics to treat neuro-disorder and slow down aging is described herein. Emerging natural products, such as quercetin, dasatinib, fisetin, piperlongumine, and curcumin, have recently been reported to be effective senolytic agents, and some structurally modified analogue of these have also been explored for better selectivity and efficacy in animal models. These showed significant potential in clinical studies and could be developed as senolytic drugs in the future.

« Previous
Graphical Abstract

[1]
Goldman, D.P.; Jay Olshansky, S. Delayed aging versus delayed disease: A new paradigm for public health. Public Policy Aging Rep., 2013, 23(4), 16-18.
[http://dx.doi.org/10.1093/ppar/23.4.16]
[2]
Wissler Gerdes, E.O.; Zhu, Y.; Tchkonia, T.; Kirkland, J.L. Discovery, development, and future application of senolytics: Theories and predictions. FEBS J., 2020, 287(12), 2418-2427.
[http://dx.doi.org/10.1111/febs.15264] [PMID: 32112672]
[3]
Robbins, P.D.; Jurk, D.; Khosla, S.; Kirkland, J.L.; LeBrasseur, N.K.; Miller, J.D.; Passos, J.F.; Pignolo, R.J.; Tchkonia, T.; Niedernhofer, L.J. Senolytic drugs: Reducing senescent cell viability to extend health span. Annu. Rev. Pharmacol. Toxicol., 2021, 61(1), 779-803.
[http://dx.doi.org/10.1146/annurev-pharmtox-050120-105018] [PMID: 32997601]
[4]
Goldman, D.P.; Cutler, D.; Rowe, J.W.; Michaud, P.C.; Sullivan, J.; Peneva, D.; Olshansky, S.J. Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health Aff., 2013, 32(10), 1698-1705.
[http://dx.doi.org/10.1377/hlthaff.2013.0052] [PMID: 24101058]
[5]
Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res., 1965, 37(3), 614-636.
[http://dx.doi.org/10.1016/0014-4827(65)90211-9] [PMID: 14315085]
[6]
Ewald, J.A.; Desotelle, J.A.; Wilding, G.; Jarrard, D.F. Therapy-induced senescence in cancer. J. Natl. Cancer Inst., 2010, 102(20), 1536-1546.
[http://dx.doi.org/10.1093/jnci/djq364] [PMID: 20858887]
[7]
He, S.; Sharpless, N.E. Senescence in Health and Disease. Cell, 2017, 169(6), 1000-1011.
[http://dx.doi.org/10.1016/j.cell.2017.05.015] [PMID: 28575665]
[8]
Dańczak-Pazdrowska, A.; Gornowicz-Porowska, J.; Polańska, A.; Krajka-Kuźniak, V.; Stawny, M.; Gostyńska, A.; Rubiś, B.; Nourredine, S.; Ashiqueali, S.; Schneider, A.; Tchkonia, T.; Wyles, S.P.; Kirkland, J.L.; Masternak, M.M. Cellular senescence in skin-related research: Targeted signaling pathways and naturally occurring therapeutic agents. Aging Cell, 2023, 22(6), e13845.
[http://dx.doi.org/10.1111/acel.13845] [PMID: 37042069]
[9]
Kuilman, T.; Michaloglou, C.; Mooi, W.J.; Peeper, D.S. The essence of senescence: Figure 1. Genes Dev., 2010, 24(22), 2463-2479.
[http://dx.doi.org/10.1101/gad.1971610] [PMID: 21078816]
[10]
Tchkonia, T.; Zhu, Y.; van Deursen, J.; Campisi, J.; Kirkland, J.L.; Van Deursen, J.; Campisi, J.; Kirkland, J.L. Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities. J. Clin. Invest., 2013, 123(3), 966-972.
[http://dx.doi.org/10.1172/JCI64098] [PMID: 23454759]
[11]
Cho, H.M.; Lee, Y.R.; Lee, B.W.; Zhang, M.; Ryu, B.; Nghiem, D.T.; Pham, H.T.T.; Oh, W.K. Phenolic constituents of the roots of rhamnoneuron balansae with senolytic activity. J. Nat. Prod., 2020, 83(12), 3661-3670.
[http://dx.doi.org/10.1021/acs.jnatprod.0c00885] [PMID: 33256407]
[12]
Kudlova, N.; De Sanctis, J.B.; Hajduch, M. Cellular senescence: Molecular targets, biomarkers, and senolytic drugs. Int. J. Mol. Sci., 2022, 23(8), 4168.
[http://dx.doi.org/10.3390/ijms23084168] [PMID: 35456986]
[13]
Muñoz-Espín, D.; Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol., 2014, 15(7), 482-496.
[http://dx.doi.org/10.1038/nrm3823] [PMID: 24954210]
[14]
He, Y.; Zheng, G.; Zhou, D. Senolytic drug development BT - senolytics in disease, ageing and longevity. In: Springer International Publishing; Muñoz-Espin, D.; Demaria, M., Eds.; Cham, 2020; pp. 3-20.
[15]
Wang, Y.; He, Y.; Rayman, M.P.; Zhang, J. Prospective selective mechanism of emerging senolytic agents derived from flavonoids. J. Agric. Food Chem., 2021, 69(42), 12418-12423.
[http://dx.doi.org/10.1021/acs.jafc.1c04379] [PMID: 34662116]
[16]
Singh, P.; Kapahi, P.; van Deursen, J.M. Immune checkpoint inhibitors as senolytic agents. Cell Res., 2022, 33(3), 197-198.
[http://dx.doi.org/10.1038/s41422-022-00761-4] [PMID: 36481795]
[17]
Prata, L.G.P.L.; Ovsyannikova, I.G.; Tchkonia, T.; Kirkland, J.L. Senescent cell clearance by the immune system: Emerging therapeutic opportunities. Semin. Immunol., 2018, 40, 101275.
[http://dx.doi.org/10.1016/j.smim.2019.04.003] [PMID: 31088710]
[18]
Rossiello, F.; Jurk, D.; Passos, J.F.; d’Adda di Fagagna, F. Telomere dysfunction in ageing and age-related diseases. Nat. Cell Biol., 2022, 24(2), 135-147.
[http://dx.doi.org/10.1038/s41556-022-00842-x] [PMID: 35165420]
[19]
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.; Roberts, L.; Tahir, S.K.; Xiao, Y.; Yang, X.; Zhang, H.; Fesik, S.; Rosenberg, S.H.; Elmore, S.W. ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res., 2008, 68(9), 3421-3428.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-5836] [PMID: 18451170]
[20]
Di Micco, R.; Krizhanovsky, V.; Baker, D.; d’Adda di Fagagna, F. Cellular senescence in ageing: From mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol., 2021, 22(2), 75-95.
[http://dx.doi.org/10.1038/s41580-020-00314-w] [PMID: 33328614]
[21]
Jackson, S.P.; Bartek, J. The DNA-damage response in human biology and disease. Nature, 2009, 461(7267), 1071-1078.
[http://dx.doi.org/10.1038/nature08467] [PMID: 19847258]
[22]
Kamijo, T.; van de Kamp, E.; Chong, M.J.; Zindy, F.; Diehl, J.A.; Sherr, C.J.; McKinnon, P.J. Loss of the ARF tumor suppressor reverses premature replicative arrest but not radiation hypersensitivity arising from disabled atm function. Cancer Res., 1999, 59(10), 2464-2469.
[PMID: 10344759]
[23]
Kamijo, T.; Zindy, F.; Roussel, M.F.; Quelle, D.E.; Downing, J.R.; Ashmun, R.A.; Grosveld, G.; Sherr, C.J. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell, 1997, 91(5), 649-659.
[http://dx.doi.org/10.1016/S0092-8674(00)80452-3] [PMID: 9393858]
[24]
Sherr, C.J. Divorcing ARF and p53: An unsettled case. Nat. Rev. Cancer, 2006, 6(9), 663-673.
[http://dx.doi.org/10.1038/nrc1954] [PMID: 16915296]
[25]
Bodnar, A.G.; Ouellette, M.; Frolkis, M.; Holt, S.E.; Chiu, C.P.; Morin, G.B.; Harley, C.B.; Shay, J.W.; Lichtsteiner, S.; Wright, W.E. Extension of life-span by introduction of telomerase into normal human cells. Science, 1998, 279, 349-352.
[26]
Hemann, M.T.; Strong, M.A.; Hao, L.Y.; Greider, C.W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell, 2001, 107(1), 67-77.
[http://dx.doi.org/10.1016/S0092-8674(01)00504-9] [PMID: 11595186]
[27]
Herbig, U.; Jobling, W.A.; Chen, B.P.C.; Chen, D.J.; Sedivy, J.M. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell, 2004, 14(4), 501-513.
[http://dx.doi.org/10.1016/S1097-2765(04)00256-4] [PMID: 15149599]
[28]
Victorelli, S.; Lagnado, A.; Halim, J.; Moore, W.; Talbot, D.; Barrett, K.; Chapman, J.; Birch, J.; Ogrodnik, M.; Meves, A.; Pawlikowski, J.S.; Jurk, D.; Adams, P.D.; van Heemst, D.; Beekman, M.; Slagboom, P.E.; Gunn, D.A.; Passos, J.F. Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. EMBO J., 2019, 38(23), e101982.
[http://dx.doi.org/10.15252/embj.2019101982] [PMID: 31633821]
[29]
Alimonti, A.; Nardella, C.; Chen, Z.; Clohessy, J.G.; Carracedo, A.; Trotman, L.C.; Cheng, K.; Varmeh, S.; Kozma, S.C.; Thomas, G.; Rosivatz, E.; Woscholski, R.; Cognetti, F.; Scher, H.I.; Pandolfi, P.P. 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), 681-693.
[http://dx.doi.org/10.1172/JCI40535] [PMID: 20197621]
[30]
Parisotto, M.; Grelet, E.; El Bizri, R.; Dai, Y.; Terzic, J.; Eckert, D.; Gargowitsch, L.; Bornert, J.M.; Metzger, D. PTEN deletion in luminal cells of mature prostate induces replication stress and senescence in vivo. J. Exp. Med., 2018, 215(6), 1749-1763.
[http://dx.doi.org/10.1084/jem.20171207] [PMID: 29743291]
[31]
Astle, M.V.; Hannan, K.M.; Ng, P.Y.; Lee, R.S.; George, A.J.; Hsu, A.K.; Haupt, Y.; Hannan, R.D.; Pearson, R.B. AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene, 2012, 31(15), 1949-1962.
[http://dx.doi.org/10.1038/onc.2011.394] [PMID: 21909130]
[32]
Suram, A.; Kaplunov, J.; Patel, P.L.; Ruan, H.; Cerutti, A.; Boccardi, V.; Fumagalli, M.; Di Micco, R.; Mirani, N.; Gurung, R.L.; Hande, M.P.; d’Adda di Fagagna, F.; Herbig, U. Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J., 2012, 31(13), 2839-2851.
[http://dx.doi.org/10.1038/emboj.2012.132] [PMID: 22569128]
[33]
Ogrunc, M.; Di Micco, R.; Liontos, M.; Bombardelli, L.; Mione, M.; Fumagalli, M.; Gorgoulis, V.G.; d’Adda di Fagagna, F. Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation. Cell Death Differ., 2014, 21(6), 998-1012.
[http://dx.doi.org/10.1038/cdd.2014.16] [PMID: 24583638]
[34]
Chan, K.T.; Blake, S.; Zhu, H.; Kang, J.; Trigos, A.S.; Madhamshettiwar, P.B.; Diesch, J.; Paavolainen, L.; Horvath, P.; Hannan, R.D.; George, A.J.; Sanij, E.; Hannan, K.M.; Simpson, K.J.; Pearson, R.B. A functional genetic screen defines the AKT-induced senescence signaling network. Cell Death Differ., 2020, 27(2), 725-741.
[http://dx.doi.org/10.1038/s41418-019-0384-8] [PMID: 31285545]
[35]
Chapman, J.; Fielder, E.; Passos, J.F. Mitochondrial dysfunction and cell senescence: Deciphering a complex relationship. FEBS Lett., 2019, 593(13), 1566-1579.
[http://dx.doi.org/10.1002/1873-3468.13498] [PMID: 31211858]
[36]
Wiley, C.D.; Velarde, M.C.; Lecot, P.; Liu, S.; Sarnoski, E.A.; Freund, A.; Shirakawa, K.; Lim, H.W.; Davis, S.S.; Ramanathan, A.; Gerencser, A.A.; Verdin, E.; Campisi, J. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab., 2016, 23(2), 303-314.
[http://dx.doi.org/10.1016/j.cmet.2015.11.011] [PMID: 26686024]
[37]
Correia-Melo, C.; Marques, F.D.M.; Anderson, R.; Hewitt, G.; Hewitt, R.; Cole, J.; Carroll, B.M.; Miwa, S.; Birch, J.; Merz, A.; Rushton, M.D.; Charles, M.; Jurk, D.; Tait, S.W.G.; Czapiewski, R.; Greaves, L.; Nelson, G.; Bohlooly-Y, M.; Rodriguez-Cuenca, S.; Vidal-Puig, A.; Mann, D.; Saretzki, G.; Quarato, G.; Green, D.R.; Adams, P.D.; von Zglinicki, T.; Korolchuk, V.I.; Passos, J.F. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J., 2016, 35(7), 724-742.
[http://dx.doi.org/10.15252/embj.201592862] [PMID: 26848154]
[38]
Ziegler, D.V.; Wiley, C.D.; Velarde, M.C. Mitochondrial effectors of cellular senescence: Beyond the free radical theory of aging. Aging Cell, 2015, 14(1), 1-7.
[http://dx.doi.org/10.1111/acel.12287] [PMID: 25399755]
[39]
Kim, H.J.; Kim, W.J.; Shin, H.R.; Yoon, H.I.; Moon, J.I.; Lee, E.; Lim, J.M.; Cho, Y.D.; Lee, M.H.; Kim, H.G.; Ryoo, H.M. ROS-induced PADI2 downregulation accelerates cellular senescence via the stimulation of SASP production and NFκB activation. Cell. Mol. Life Sci., 2022, 79(3), 155.
[http://dx.doi.org/10.1007/s00018-022-04186-5]
[40]
Wang, Y.; Sui, Y.; Niu, Y.; Liu, D.; Xu, Q.; Liu, F.; Zuo, K.; Liu, M.; Sun, W.; Wang, Z.; Liu, Z.; Zou, F.; Shi, J.; Liu, X.; Liu, J. PBX1-SIRT1 positive feedback loop attenuates ROS-mediated HF-MSC senescence and apoptosis. Stem Cell Rev. Rep., 2023, 19(2), 443-454.
[http://dx.doi.org/10.1007/s12015-022-10425-w] [PMID: 35962175]
[41]
Liu, R.M. Aging, cellular senescence, and alzheimer’s disease. Int. J. Mol. Sci., 2022, 23(4), 1989.
[http://dx.doi.org/10.3390/ijms23041989] [PMID: 35216123]
[42]
Martini, H.; Passos, J.F. Cellular senescence: All roads lead to mitochondria. FEBS J., 2023, 290(5), 1186-1202.
[http://dx.doi.org/10.1111/febs.16361] [PMID: 35048548]
[43]
Kirkland, J.L.; Tchkonia, T.; Zhu, Y.; Niedernhofer, L.J.; Robbins, P.D. The clinical potential of senolytic drugs. J. Am. Geriatr. Soc., 2017, 65(10), 2297-2301.
[http://dx.doi.org/10.1111/jgs.14969] [PMID: 28869295]
[44]
Chaib, S.; Tchkonia, T.; Kirkland, J.L. Cellular senescence and senolytics: The path to the clinic. Nat. Med., 2022, 28(8), 1556-1568.
[http://dx.doi.org/10.1038/s41591-022-01923-y] [PMID: 35953721]
[45]
Niedernhofer, L.J.; Robbins, P.D. Senotherapeutics for healthy ageing. Nat. Rev. Drug Discov., 2018, 17(5), 377.
[http://dx.doi.org/10.1038/nrd.2018.44] [PMID: 29651106]
[46]
Sigalapalli, D.K.; Kiranmai, G.; Tokala, R.; Tripura, C.; Ambatwar, R.; Nunewar, S.N.; Kadagathur, M.; Shankaraiah, N.; Nagesh, N.; Nagendra Babu, B.; Tangellamudi, N.D. Targeting tubulin polymerization and DNA binding of 4-thiazolidinone–umbelliferone hybrids: synthesis and cytotoxicity evaluation. New J. Chem., 2021, 45(40), 18908-18923.
[http://dx.doi.org/10.1039/D1NJ03135J]
[47]
Hickson, L.J.; Langhi Prata, L.G.P.; Bobart, S.A.; Evans, T.K.; Giorgadze, N.; Hashmi, S.K.; Herrmann, S.M.; Jensen, M.D.; Jia, Q.; Jordan, K.L.; Kellogg, T.A.; Khosla, S.; Koerber, D.M.; Lagnado, A.B.; Lawson, D.K.; LeBrasseur, N.K.; Lerman, L.O.; McDonald, K.M.; McKenzie, T.J.; Passos, J.F.; Pignolo, R.J.; Pirtskhalava, T.; Saadiq, I.M.; Schaefer, K.K.; Textor, S.C.; Victorelli, S.G.; Volkman, T.L.; Xue, A.; Wentworth, M.A.; Wissler Gerdes, E.O.; Zhu, Y.; Tchkonia, T.; Kirkland, J.L. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine, 2019, 47, 446-456.
[http://dx.doi.org/10.1016/j.ebiom.2019.08.069] [PMID: 31542391]
[48]
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.; McGuckian, C.; Wade, E.A.; Kato, J.I.; Grassi, D.; Wentworth, M.; Burd, C.E.; Arriaga, E.A.; Ladiges, W.L.; Tchkonia, T.; Kirkland, J.L.; Robbins, P.D.; Niedernhofer, L.J. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018, 36, 18-28.
[http://dx.doi.org/10.1016/j.ebiom.2018.09.015] [PMID: 30279143]
[49]
Zhang, X.; Zhang, S.; Liu, X.; Wang, Y.; Chang, J.; Zhang, X.; Mackintosh, S.G.; Tackett, A.J.; He, Y.; Lv, D.; Laberge, R.M.; Campisi, J.; Wang, J.; Zheng, G.; Zhou, D. Oxidation resistance 1 is a novel senolytic target. Aging Cell, 2018, 17(4), e12780.
[http://dx.doi.org/10.1111/acel.12780] [PMID: 29766639]
[50]
Grill, A.E.; Shahani, K.; Koniar, B.; Panyam, J. Chemopreventive efficacy of curcumin-loaded PLGA microparticles in a transgenic mouse model of HER-2-positive breast cancer. Drug Deliv. Transl. Res., 2018, 8(2), 329-341.
[http://dx.doi.org/10.1007/s13346-017-0377-4] [PMID: 28417445]
[51]
Triana-Martínez, F.; Picallos-Rabina, P.; Da Silva-Álvarez, S.; Pietrocola, F.; Llanos, S.; Rodilla, V.; Soprano, E.; Pedrosa, P.; Ferreirós, A.; Barradas, M.; Hernández-González, F.; Lalinde, M.; Prats, N.; Bernadó, C.; González, P.; Gómez, M.; Ikonomopoulou, M.P.; Fernández-Marcos, P.J.; García-Caballero, T.; del Pino, P.; Arribas, J.; Vidal, A.; González-Barcia, M.; Serrano, M.; Loza, M.I.; Domínguez, E.; Collado, M. Identification and characterization of Cardiac Glycosides as senolytic compounds. Nat. Commun., 2019, 10(1), 4731.
[http://dx.doi.org/10.1038/s41467-019-12888-x] [PMID: 31636264]
[52]
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.; Onken, J.L.; Johnson, K.O.; Verzosa, G.C.; Langhi, L.G.P.; Weigl, M.; Giorgadze, N.; LeBrasseur, N.K.; Miller, J.D.; Jurk, D.; Singh, R.J.; Allison, D.B.; Ejima, K.; Hubbard, G.B.; Ikeno, Y.; Cubro, H.; Garovic, V.D.; Hou, X.; Weroha, S.J.; Robbins, P.D.; Niedernhofer, L.J.; Khosla, S.; Tchkonia, T.; Kirkland, J.L. Senolytics improve physical function and increase lifespan in old age. Nat. Med., 2018, 24(8), 1246-1256.
[http://dx.doi.org/10.1038/s41591-018-0092-9] [PMID: 29988130]
[53]
Zhu, Y.; Tchkonia, T.; Pirtskhalava, T.; Gower, A.C.; Ding, H.; Giorgadze, N.; Palmer, A.K.; Ikeno, Y.; Hubbard, G.B.; Lenburg, M.; O’Hara, S.P.; LaRusso, N.F.; Miller, J.D.; Roos, C.M.; Verzosa, G.C.; LeBrasseur, N.K.; Wren, J.D.; Farr, J.N.; Khosla, S.; Stout, M.B.; McGowan, S.J.; Fuhrmann-Stroissnigg, H.; Gurkar, A.U.; Zhao, J.; Colangelo, D.; Dorronsoro, A.; Ling, Y.Y.; Barghouthy, A.S.; Navarro, D.C.; Sano, T.; Robbins, P.D.; Niedernhofer, L.J.; Kirkland, J.L. The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell, 2015, 14(4), 644-658.
[http://dx.doi.org/10.1111/acel.12344] [PMID: 25754370]
[54]
Fuhrmann-Stroissnigg, H.; Ling, Y.Y.; Zhao, J.; McGowan, S.J.; Zhu, Y.; Brooks, R.W.; Grassi, D.; Gregg, S.Q.; Stripay, J.L.; Dorronsoro, A.; Corbo, L.; Tang, P.; Bukata, C.; Ring, N.; Giacca, M.; Li, X.; Tchkonia, T.; Kirkland, J.L.; Niedernhofer, L.J.; Robbins, P.D. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun., 2017, 8(1), 422.
[http://dx.doi.org/10.1038/s41467-017-00314-z] [PMID: 28871086]
[55]
Jeon, O.H.; Kim, C.; Laberge, R.M.; Demaria, M.; Rathod, S.; Vasserot, A.P.; Chung, J.W.; Kim, D.H.; Poon, Y.; David, N.; Baker, D.J.; van Deursen, J.M.; Campisi, J.; Elisseeff, J.H. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med., 2017, 23(6), 775-781.
[http://dx.doi.org/10.1038/nm.4324] [PMID: 28436958]
[56]
Pawge, G.; Khatik, G.L. p53 regulated senescence mechanism and role of its modulators in age-related disorders. Biochem. Pharmacol., 2021, 190, 114651.
[http://dx.doi.org/10.1016/j.bcp.2021.114651] [PMID: 34118220]
[57]
Baar, M.P.; Brandt, R.M.C.; Putavet, D.A.; Klein, J.D.D.; Derks, K.W.J.; Bourgeois, B.R.M.; Stryeck, S.; Rijksen, Y.; van Willigenburg, H.; Feijtel, D.A.; van der Pluijm, I.; Essers, J.; van Cappellen, W.A.; van IJcken, W.F.; Houtsmuller, A.B.; Pothof, J.; de Bruin, R.W.F.; Madl, T.; Hoeijmakers, J.H.J.; Campisi, J.; de Keizer, P.L.J. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell, 2017, 169(1), 132-147.e16.
[http://dx.doi.org/10.1016/j.cell.2017.02.031] [PMID: 28340339]
[58]
Parasuraman, S.; Anand David, A.V.; Arulmoli, R.; Parasuraman, S. Overviews of biological importance of quercetin: A bioactive flavonoid. Pharmacogn. Rev., 2016, 10(20), 84-89.
[http://dx.doi.org/10.4103/0973-7847.194044] [PMID: 28082789]
[59]
Arita, M.; Takebe, Y.; Wakita, T.; Shimizu, H. A bifunctional anti-enterovirus compound that inhibits replication and the early stage of enterovirus 71 infection. J. Gen. Virol., 2010, 91(11), 2734-2744.
[http://dx.doi.org/10.1099/vir.0.023374-0] [PMID: 20660150]
[60]
Fernández-Palanca, P.; Fondevila, F.; Méndez-Blanco, C.; Tuñón, M.J.; González-Gallego, J.; Mauriz, J.L. Antitumor effects of quercetin in hepatocarcinoma in vitro and in vivo models: A systematic review. Nutrients, 2019, 11(12), 2875.
[http://dx.doi.org/10.3390/nu11122875] [PMID: 31775362]
[61]
Silva, E.C.B.; Cajueiro, J.F.P.; Silva, S.V.; Soares, P.C.; Guerra, M.M.P. Effect of antioxidants resveratrol and quercetin on in vitro evaluation of frozen ram sperm. Theriogenology, 2012, 77(8), 1722-1726.
[http://dx.doi.org/10.1016/j.theriogenology.2011.11.023] [PMID: 22289215]
[62]
Wang, W.; Sun, C.; Mao, L.; Ma, P.; Liu, F.; Yang, J.; Gao, Y. The biological activities, chemical stability, metabolism and delivery systems of quercetin: A review. Trends Food Sci. Technol., 2016, 56, 21-38.
[http://dx.doi.org/10.1016/j.tifs.2016.07.004]
[63]
Hwang, H.V.; Tran, D.T.; Rebuffatti, M.N.; Li, C.S.; Knowlton, A.A. Investigation of quercetin and hyperoside as senolytics in adult human endothelial cells. PLoS One, 2018, 13(1), e0190374.
[http://dx.doi.org/10.1371/journal.pone.0190374] [PMID: 29315311]
[64]
Grezella, C.; Fernandez-Rebollo, E.; Franzen, J.; Ventura Ferreira, M.S.; Beier, F.; Wagner, W.; Wagner, W. Effects of senolytic drugs on human mesenchymal stromal cells. Stem Cell Res. Ther., 2018, 9(1), 108.
[http://dx.doi.org/10.1186/s13287-018-0857-6] [PMID: 29669575]
[65]
Kumar, S.; Ambatwar, R.; Gupta, V.; Khatik, G.L. Convenient “ on - Water ” One - Pot, Synthesis of Flavonols. Res. Chem. Intermed., 2023, 49, 901-915.
[http://dx.doi.org/10.1007/s11164-022-04932-1]
[66]
Shao, Z.; Wang, B.; Shi, Y.; Xie, C.; Huang, C.; Chen, B.; Zhang, H.; Zeng, G.; Liang, H.; Wu, Y.; Zhou, Y.; Tian, N.; Wu, A.; Gao, W.; Wang, X.; Zhang, X. Senolytic agent quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-κB axis. Osteoarthr. Cartil. , 2021, 29(3), 413-422.
[http://dx.doi.org/10.1016/j.joca.2020.11.006] [PMID: 33242601]
[67]
Kumari, S.; Kamboj, A. Protective role of fisetin in STZ induced diabetic nephropathy in rats protective role of fisetin in STZ induced diabetic nephropathy in rats. J. Pharm. Res., 2021, 97-111.
[68]
Sinha, R.; Srivastava, S.; Joshi, A.; Joshi, U.J.; Govil, G. in-vitro anti-proliferative and anti-oxidant activity of galangin, fisetin and quercetin: Role of localization and intermolecular interaction in model membrane. Eur. J. Med. Chem., 2014, 79, 102-109.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.002] [PMID: 24727463]
[69]
Shaikh, F.; Shastri, S.L.; Naik, N.S.; Kulkarni, R.; Madar, J.M.; Shastri, L.A.; Joshi, S.D.; Sunagar, V. Synthesis, antitubercular and antimicrobial activity of 1,2,4-triazolidine-3-thione functionalized coumarin and phenyl derivatives and molecular docking studies. ChemistrySelect, 2019, 4(1), 105-115.
[http://dx.doi.org/10.1002/slct.201802395]
[70]
Senescence, C.; Gallorini, M. Fisetin as a senotherapeutic agent : Biopharmaceutical and neuroprotection. Molecules, 2022, 27, 738.
[http://dx.doi.org/10.3390/molecules27030738] [PMID: 35164003]
[71]
Arai, Y.; Watanabe, S.; Kimira, M.; Shimoi, K.; Mochizuki, R.; Kinae, N. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J. Nutr., 2000, 130(9), 2243-2250.
[http://dx.doi.org/10.1093/jn/130.9.2243] [PMID: 10958819]
[72]
Sundarraj, K.; Raghunath, A.; Perumal, E. Biomedicine & pharmacotherapy a review on the chemotherapeutic potential of Fi Setin : in vitro evidences. Biomed. Pharmacother., 2018, 97, 928-940.
[http://dx.doi.org/10.1016/j.biopha.2017.10.164] [PMID: 29136771]
[73]
Lall, R.K.; Adhami, V.M.; Mukhtar, H. Dietary flavonoid fisetin for cancer prevention and treatment. Mol. Nutr. Food Res., 2016, 60(6), 1396-1405.
[http://dx.doi.org/10.1002/mnfr.201600025] [PMID: 27059089]
[74]
Reddy, K.T.K.; Haque, M.A. Bioanalytical Method Development and Validation of Atrasentan in Human Plasma Using Verapamil as Internal Standard by Liquid Chromatography Coupled with Tandem Mass Spectrometry. Int. J. Health Sci. (Qassim), 2022, 6, 625-638.
[75]
Reddy, K.T.K.; Haque, M.A. Develop and validate a highly sensitive method for the estimation of molnupiravir in rat plasma by high-performance liquid chromatography-tandem mass spectroscopy and its application to pharmacokinetic studies. J. Pharm. Negat. Results, 2022, 13, 28-34.
[76]
Montero, J.C.; Seoane, S.; Ocaña, A.; Pandiella, A. Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: Possible combinations in solid tumors. Clin. Cancer Res., 2011, 17(17), 5546-5552.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-2616] [PMID: 21670084]
[77]
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, 2016, 8(11), 2915-2926.
[http://dx.doi.org/10.18632/aging.101100] [PMID: 27913811]
[78]
Ji, L.; Qu, L.; Wang, C.; Peng, W.; Li, S.; Yang, H.; Luo, H.; Yin, F.; Lu, D.; Liu, X.; Kong, L.; Wang, X. Identification and optimization of piperlongumine analogues as potential antioxidant and anti-inflammatory agents via activation of Nrf2. Eur. J. Med. Chem., 2021, 210, 112965.
[http://dx.doi.org/10.1016/j.ejmech.2020.112965] [PMID: 33148493]
[79]
Sun, A.L.; Mu, W.W.; Li, Y.M.; Sun, Y.L.; Li, P.X.; Liu, R.M.; Yang, J.; Liu, G.Y. Piperlongumine analogs promote A549 cell apoptosis through enhancing ROS generation. Molecules, 2021, 26(11), 3243.
[http://dx.doi.org/10.3390/molecules26113243] [PMID: 34071298]
[80]
Qin, J.; Li, H.; Wang, X.; Zhang, Y.; Duan, Y.; Yao, Y.; Yang, H.; Sun, M. Discovery of a novel piperlongumine analogue as a microtubule polymerization inhibitor with potent anti-angiogenic and anti-metastatic efficacy. Eur. J. Med. Chem., 2022, 243, 114738.
[http://dx.doi.org/10.1016/j.ejmech.2022.114738] [PMID: 36162214]
[81]
Tripathi, S.K.; Biswal, B.K. Piperlongumine, a potent anticancer phytotherapeutic: Perspectives on contemporary status and future possibilities as an anticancer agent. Pharmacol. Res., 2020, 156, 104772.
[http://dx.doi.org/10.1016/j.phrs.2020.104772] [PMID: 32283222]
[82]
Wang, F.; Mao, Y.; You, Q.; Hua, D.; Cai, D. Piperlongumine induces apoptosis and autophagy in human lung cancer cells through inhibition of PI3K/Akt/mTOR pathway. Int. J. Immunopathol. Pharmacol., 2015, 28(3), 362-373.
[http://dx.doi.org/10.1177/0394632015598849] [PMID: 26246196]
[83]
Zhu, P.; Qian, J.; Xu, Z.; Meng, C.; Zhu, W.; Ran, F.; Zhang, W.; Zhang, Y.; Ling, Y. Overview of piperlongumine analogues and their therapeutic potential. Eur. J. Med. Chem., 2021, 220, 113471.
[http://dx.doi.org/10.1016/j.ejmech.2021.113471] [PMID: 33930801]
[84]
Lone, F.A.; Agrawal, H.; Parihar, D. Effect of piperine supplementation on monensin induced stress using invitro culture method. Int. J. Res. Eng. Sci. Manag., 2018, 1, 113-117.
[85]
Zhang, L.; Liu, C.; Yuan, M.; Huang, C.; Chen, L.; Su, T.; Liao, Z.; Gan, L. Piperlongumine produces antidepressant-like effects in rats exposed to chronic unpredictable stress. Behav. Pharmacol., 2019, 30(8), 721-728.
[http://dx.doi.org/10.1097/FBP.0000000000000498] [PMID: 31503069]
[86]
Liu, X.; Wang, Y.; Zhang, X.; Gao, Z.; Zhang, S.; Shi, P.; Zhang, X.; Song, L.; Hendrickson, H.; Zhou, D.; Zheng, G. Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation. Bioorg. Med. Chem., 2018, 26(14), 3925-3938.
[http://dx.doi.org/10.1016/j.bmc.2018.06.013] [PMID: 29925484]
[87]
Aggarwal, B.B.; Harikumar, K.B.; Harikumar, K.B. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int. J. Biochem. Cell Biol., 2009, 41(1), 40-59.
[http://dx.doi.org/10.1016/j.biocel.2008.06.010] [PMID: 18662800]
[88]
Weber, W.M.; Hunsaker, L.A.; Abcouwer, S.F.; Deck, L.M.; Vander Jagt, D.L. Anti-oxidant activities of curcumin and related enones. Bioorg. Med. Chem., 2005, 13(11), 3811-3820.
[http://dx.doi.org/10.1016/j.bmc.2005.03.035] [PMID: 15863007]
[89]
Wu, J.; Wu, S.; Shi, L.; Zhang, S.; Ren, J.; Yao, S.; Yun, D.; Huang, L.; Wang, J.; Li, W.; Wu, X.; Qiu, P.; Liang, G. Design, synthesis, and evaluation of asymmetric EF24 analogues as potential anti-cancer agents for lung cancer. Eur. J. Med. Chem., 2017, 125, 1321-1331.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.027] [PMID: 27886548]
[90]
Mdzinarishvili, A.; Houson, H.; Hedrick, A.; Awasthi, V. Evaluation of anti-inflammatory diphenyldihaloketone EF24 in transient ischemic stroke model. Brain Inj., 2022, 36(2), 279-286.
[http://dx.doi.org/10.1080/02699052.2022.2034959] [PMID: 35254869]
[91]
Gupta, V.; Ambatwar, R.; Bhanwala, N.; Khatik, G.L. Coumarin as a privileged and medicinally important scaffold in the treatment of tuberculosis. Curr. Top. Med. Chem., 2023, 23(16), 1489-1502.
[http://dx.doi.org/10.2174/1568026623666230330084058] [PMID: 37005527]
[92]
Li, W.; He, Y.; Zhang, R.; Zheng, G.; Zhou, D. The curcumin analog EF24 is a novel senolytic agent. Aging, 2019, 11(2), 771-782.
[http://dx.doi.org/10.18632/aging.101787] [PMID: 30694217]
[93]
Sharma, A.K.; Roberts, R.L.; Benson, R.D., Jr; Pierce, J.L.; Yu, K.; Hamrick, M.W.; McGee-Lawrence, M.E. The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone Loss and Impaired Osteoprogenitor Function in Aged Mice. Front. Cell Dev. Biol., 2020, 8, 354.
[http://dx.doi.org/10.3389/fcell.2020.00354] [PMID: 32509782]
[94]
Shi, J.; Zhou, Y.; Huang, H.C.; Mitchison, T.J. Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL. Cancer Res., 2011, 71(13), 4518-4526.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-4336] [PMID: 21546570]
[95]
Gandhi, L.; Camidge, D.R.; Ribeiro de Oliveira, M.; Bonomi, P.; Gandara, D.; Khaira, D.; Hann, C.L.; McKeegan, E.M.; Litvinovich, E.; Hemken, P.M.; Dive, C.; Enschede, S.H.; Nolan, C.; Chiu, Y.L.; Busman, T.; Xiong, H.; Krivoshik, A.P.; Humerickhouse, R.; Shapiro, G.I.; Rudin, C.M.; Phase, I. Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J. Clin. Oncol., 2011, 29(7), 909-916.
[http://dx.doi.org/10.1200/JCO.2010.31.6208] [PMID: 21282543]
[96]
Joly, F.; Fabbro, M.; Follana, P.; Lequesne, J.; Medioni, J.; Lesoin, A.; Frenel, J.S.; Abadie-Lacourtoisie, S.; Floquet, A.; Gladieff, L.; You, B.; Gavoille, C.; Kalbacher, E.; Briand, M.; Brachet, P.E.; Giffard, F.; Weiswald, L.B.; Just, P.A.; Blanc-Fournier, C.; Leconte, A.; Clarisse, B.; Leary, A.; Poulain, L. A phase II study of Navitoclax (ABT-263) as single agent in women heavily pretreated for recurrent epithelial ovarian cancer: The MONAVI – GINECO study. Gynecol. Oncol., 2022, 165(1), 30-39.
[http://dx.doi.org/10.1016/j.ygyno.2022.01.021] [PMID: 35123771]
[97]
Saleh, T.; Carpenter, V.J.; Tyutyunyk-Massey, L.; Murray, G.; Leverson, J.D.; Souers, A.J.; Alotaibi, M.R.; Faber, A.C.; Reed, J.; Harada, H.; Gewirtz, D.A. Clearance of therapy-induced senescent tumor cells by the senolytic ABT-263 via interference with BCL-X L –BAX interaction. Mol. Oncol., 2020, 14(10), 2504-2519.
[http://dx.doi.org/10.1002/1878-0261.12761] [PMID: 32652830]
[98]
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. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging, 2017, 9(3), 955-963.
[http://dx.doi.org/10.18632/aging.101202] [PMID: 28273655]
[99]
Chang, J.; Wang, Y.; Shao, L.; Laberge, R.M.; Demaria, M.; Campisi, J.; Janakiraman, K.; Sharpless, N.E.; Ding, S.; Feng, W.; Luo, Y.; Wang, X.; Aykin-Burns, N.; Krager, K.; Ponnappan, U.; Hauer-Jensen, M.; Meng, A.; Zhou, D. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med., 2016, 22(1), 78-83.
[http://dx.doi.org/10.1038/nm.4010] [PMID: 26657143]
[100]
Guerrero, A.; Herranz, N.; Sun, B.; Wagner, V.; Gallage, S.; Guiho, R.; Wolter, K.; Pombo, J.; Irvine, E.E.; Innes, A.J.; Birch, J.; Glegola, J.; Manshaei, S.; Heide, D.; Dharmalingam, G.; Harbig, J.; Olona, A.; Behmoaras, J.; Dauch, D.; Uren, A.G.; Zender, L.; Vernia, S.; Martínez-Barbera, J.P.; Heikenwalder, M.; Withers, D.J.; Gil, J. Cardiac glycosides are broad-spectrum senolytics. Nat. Metab., 2019, 1(11), 1074-1088.
[http://dx.doi.org/10.1038/s42255-019-0122-z] [PMID: 31799499]
[101]
Vilgelm, A.E.; Pawlikowski, J.S.; Liu, Y.; Hawkins, O.E.; Davis, T.A.; Smith, J.; Weller, K.P.; Horton, L.W.; McClain, C.M.; Ayers, G.D.; Turner, D.C.; Essaka, D.C.; Stewart, C.F.; Sosman, J.A.; Kelley, M.C.; Ecsedy, J.A.; Johnston, J.N.; Richmond, A. Mdm2 and aurora kinase a inhibitors synergize to block melanoma growth by driving apoptosis and immune clearance of tumor cells. Cancer Res., 2015, 75(1), 181-193.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-2405] [PMID: 25398437]
[102]
Fuhrmann-Stroissnigg, H.; Santiago, F.E.; Grassi, D.; Ling, Y.; Niedernhofer, L.J.; Robbins, P.D. SA-β-galactosidase-based screening assay for the identification of senotherapeutic drugs. J. Vis. Exp., 2019, 148(148)
[http://dx.doi.org/10.3791/58133] [PMID: 31305507]
[103]
Weiland, T.; Lampe, J.; Essmann, F.; Venturelli, S.; Berger, A.; Bossow, S.; Berchtold, S.; Schulze-Osthoff, K.; Lauer, U.M.; Bitzer, M. Enhanced killing of therapy-induced senescent tumor cells by oncolytic measles vaccine viruses. Int. J. Cancer, 2014, 134(1), 235-243.
[http://dx.doi.org/10.1002/ijc.28350] [PMID: 23797800]
[104]
Chen, Z.; Hu, K.; Feng, L.; Su, R.; Lai, N.; Yang, Z.; Kang, S. Senescent cells re-engineered to express soluble programmed death receptor-1 for inhibiting programmed death receptor-1/programmed death ligand-1 as a vaccination approach against breast cancer. Cancer Sci., 2018, 109(6), 1753-1763.
[http://dx.doi.org/10.1111/cas.13618] [PMID: 29675979]
[105]
Muñoz-Espín, D.; Rovira, M.; Galiana, I.; Giménez, C.; Lozano-Torres, B.; Paez-Ribes, M.; Llanos, S.; Chaib, S.; Muñoz-Martín, M.; Ucero, A.C.; Garaulet, G.; Mulero, F.; Dann, S.G.; VanArsdale, T.; Shields, D.J.; Bernardos, A.; Murguía, J.R.; Martínez-Máñez, R.; Serrano, M. A versatile drug delivery system targeting senescent cells. EMBO Mol. Med., 2018, 10(9), e9355.
[http://dx.doi.org/10.15252/emmm.201809355] [PMID: 30012580]
[106]
Nakagami, H. Cellular senescence and senescence-associated T cells as a potential therapeutic target. Geriatr. Gerontol. Int., 2020, 20(2), 97-100.
[http://dx.doi.org/10.1111/ggi.13851] [PMID: 31837250]
[107]
He, Y.; Li, W.; Lv, D.; Zhang, X.; Zhang, X.; Ortiz, Y.T.; Budamagunta, V.; Campisi, J.; Zheng, G.; Zhou, D. Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity. Aging Cell, 2020, 19(3), e13117.
[http://dx.doi.org/10.1111/acel.13117] [PMID: 32064756]
[108]
Johmura, Y.; Yamanaka, T.; Omori, S.; Wang, T.W.; Sugiura, Y.; Matsumoto, M.; Suzuki, N.; Kumamoto, S.; Yamaguchi, K.; Hatakeyama, S.; Takami, T.; Yamaguchi, R.; Shimizu, E.; Ikeda, K.; Okahashi, N.; Mikawa, R.; Suematsu, M.; Arita, M.; Sugimoto, M.; Nakayama, K.I.; Furukawa, Y.; Imoto, S.; Nakanishi, M. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science, 2021, 371, 265-270.
[109]
Wakita, M.; Takahashi, A.; Sano, O.; Loo, T.M.; Imai, Y.; Narukawa, M.; Iwata, H.; Matsudaira, T.; Kawamoto, S.; Ohtani, N.; Yoshimori, T.; Hara, E. A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. Nat. Commun., 2020, 11(1), 1935.
[http://dx.doi.org/10.1038/s41467-020-15719-6] [PMID: 32321921]
[110]
Baar, M.P.; Brandt, R.M.C.; Putavet, D.A.; Klein, J.D.D.; Derks, K.W.J.; Bourgeois, B.R.M.; Stryeck, S.; Rijksen, Y.; van Willigenburg, H.; Feijtel, D.A. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 2017, 169, 132–147. e16.
[111]
Igney, F.H.; Krammer, P.H. Death and anti-death: Tumour resistance to apoptosis. Nat. Rev. Cancer, 2002, 2(4), 277-288.
[http://dx.doi.org/10.1038/nrc776] [PMID: 12001989]
[112]
Czabotar, P.E.; Lessene, G.; Strasser, A.; Adams, J.M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol., 2014, 15(1), 49-63.
[http://dx.doi.org/10.1038/nrm3722] [PMID: 24355989]
[113]
Bussian, T.J.; Aziz, A.; Meyer, C.F.; Swenson, B.L.; van Deursen, J.M.; Baker, D.J. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature, 2018, 562(7728), 578-582.
[http://dx.doi.org/10.1038/s41586-018-0543-y] [PMID: 30232451]
[114]
Mason, K.D.; Carpinelli, M.R.; Fletcher, J.I.; Collinge, J.E.; Hilton, A.A.; Ellis, S.; Kelly, P.N.; Ekert, P.G.; Metcalf, D.; Roberts, A.W.; Huang, D.C.S.; Kile, B.T. Programmed anuclear cell death delimits platelet life span. Cell, 2007, 128(6), 1173-1186.
[http://dx.doi.org/10.1016/j.cell.2007.01.037] [PMID: 17382885]
[115]
Zhang, H.; Nimmer, P.M.; Tahir, S.K.; Chen, J.; Fryer, R.M.; Hahn, K.R.; Iciek, L.A.; Morgan, S.J.; Nasarre, M.C.; Nelson, R.; Preusser, L.C.; Reinhart, G.A.; Smith, M.L.; Rosenberg, S.H.; Elmore, S.W.; Tse, C. Bcl-2 family proteins are essential for platelet survival. Cell Death Differ., 2007, 14(5), 943-951.
[http://dx.doi.org/10.1038/sj.cdd.4402081] [PMID: 17205078]
[116]
Johmura, Y.; Nakanishi, M. Multiple facets of p53 in senescence induction and maintenance. Cancer Sci., 2016, 107(11), 1550-1555.
[http://dx.doi.org/10.1111/cas.13060] [PMID: 27560979]
[117]
Kim, R.H.; Kang, M.K.; Kim, T.; Yang, P.; Bae, S.; Williams, D.W.; Phung, S.; Shin, K.H.; Hong, C.; Park, N.H. Regulation of p53 during senescence in normal human keratinocytes. Aging Cell, 2015, 14(5), 838-846.
[http://dx.doi.org/10.1111/acel.12364] [PMID: 26138448]
[118]
Schwarze, S.R.; Shi, Y.; Fu, V.X.; Watson, P.A.; Jarrard, D.F. Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. Oncogene, 2001, 20(57), 8184-8192.
[http://dx.doi.org/10.1038/sj.onc.1205049] [PMID: 11781834]
[119]
Fridman, J.S.; Lowe, S.W. Control of apoptosis by p53. Oncogene, 2003, 22(56), 9030-9040.
[http://dx.doi.org/10.1038/sj.onc.1207116] [PMID: 14663481]
[120]
Kruse, J.P.; Gu, W. Modes of p53 regulation. Cell, 2009, 137(4), 609-622.
[http://dx.doi.org/10.1016/j.cell.2009.04.050] [PMID: 19450511]
[121]
Tisato, V.; Voltan, R.; Gonelli, A.; Secchiero, P.; Zauli, G. MDM2/X inhibitors under clinical evaluation: Perspectives for the management of hematological malignancies and pediatric cancer. J. Hematol. Oncol., 2017, 10(1), 133.
[http://dx.doi.org/10.1186/s13045-017-0500-5] [PMID: 28673313]
[122]
Li, Y.; Yang, J.; Aguilar, A.; McEachern, D.; Przybranowski, S.; Liu, L.; Yang, C.Y.; Wang, M.; Han, X.; Wang, S. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression. J. Med. Chem., 2019, 62(2), 448-466.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00909] [PMID: 30525597]
[123]
Eijkelenboom, A.; Burgering, B.M.T. FOXOs: Signalling integrators for homeostasis maintenance. Nat. Rev. Mol. Cell Biol., 2013, 14(2), 83-97.
[http://dx.doi.org/10.1038/nrm3507] [PMID: 23325358]
[124]
de Keizer, P.L.J.; Burgering, B.M.T.; Dansen, T.B. Forkhead box o as a sensor, mediator, and regulator of redox signaling. Antioxid. Redox Signal., 2011, 14(6), 1093-1106.
[http://dx.doi.org/10.1089/ars.2010.3403] [PMID: 20626320]
[125]
Martins, R.; Lithgow, G.J.; Link, W. Long live FOXO : Unraveling the role of FOXO proteins in aging and longevity. Aging Cell, 2016, 15(2), 196-207.
[http://dx.doi.org/10.1111/acel.12427] [PMID: 26643314]
[126]
Macario, A.J.L.; De Macario, E.C. Center of Marine Biotechnology, University of Maryland Biotechnology Institute, Baltimore, MD 21202, USA. Biotechnology, 2007, 2588-2600.
[127]
Wu, J.; Liu, T.; Rios, Z.; Mei, Q.; Lin, X.; Cao, S. Heat shock proteins and cancer. Trends Pharmacol. Sci., 2017, 38(3), 226-256.
[http://dx.doi.org/10.1016/j.tips.2016.11.009] [PMID: 28012700]
[128]
Whitesell, L.; Lindquist, S.L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer, 2005, 5(10), 761-772.
[http://dx.doi.org/10.1038/nrc1716] [PMID: 16175177]
[129]
Neckers, L.; Workman, P. Hsp90 molecular chaperone inhibitors: Are we there yet? Clin. Cancer Res., 2012, 18(1), 64-76.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1000] [PMID: 22215907]
[130]
Sanchez, J.; Carter, T.R.; Cohen, M.S.; Blagg, B.S.J. Old and new approaches to target the hsp90 chaperone. Curr. Cancer Drug Targets, 2020, 20(4), 253-270.
[http://dx.doi.org/10.2174/1568009619666191202101330] [PMID: 31793427]
[131]
Chauhan, D.; Tian, Z.; Nicholson, B.; Kumar, K.G.S.; Zhou, B.; Carrasco, R.; McDermott, J.L.; Leach, C.A.; Fulcinniti, M.; Kodrasov, M.P.; Weinstock, J.; Kingsbury, W.D.; Hideshima, T.; Shah, P.K.; Minvielle, S.; Altun, M.; Kessler, B.M.; Orlowski, R.; Richardson, P.; Munshi, N.; Anderson, K.C.; Article, A. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell, 2012, 22(3), 345-358.
[http://dx.doi.org/10.1016/j.ccr.2012.08.007] [PMID: 22975377]
[132]
Fan, Y-H.; Cheng, J.; Vasudevan, S.A.; Dou, J.; Zhang, H.; Patel, R.H.; Ma, I.T.; Rojas, Y.; Zhao, Y.; Yu, Y.; Zhang, H.; Shohet, J.M.; Nuchtern, J.G.; Kim, E.S.; Yang, J. USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis. Cell Death Dis., 2013, 4(10), e867.
[http://dx.doi.org/10.1038/cddis.2013.400] [PMID: 24136231]
[133]
Tavana, O.; Li, D.; Dai, C.; Lopez, G.; Banerjee, D.; Kon, N.; Chen, C.; Califano, A.; Yamashiro, D.J.; Sun, H.; Gu, W. HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma. Nat. Med., 2016, 22(10), 1180-1186.
[http://dx.doi.org/10.1038/nm.4180] [PMID: 27618649]
[134]
Zhou, J.; Wang, J.; Chen, C.; Yuan, H.; Wen, X.; Sun, H. USP7: Target validation and drug discovery for cancer therapy. Med. Chem., 2018, 14(1), 3-18.
[PMID: 29065837]
[135]
Oliver, P.L.; Finelli, M.J.; Edwards, B.; Bitoun, E.; Butts, D.L.; Becker, E.B.E.; Cheeseman, M.T.; Davies, B.; Davies, K.E. Oxr1 is essential for protection against oxidative stress-induced neurodegeneration. PLoS Genet., 2011, 7(10), e1002338.
[http://dx.doi.org/10.1371/journal.pgen.1002338] [PMID: 22028674]
[136]
Hanks, S.K.; Quinn, A.M. Protein kinase catalytic domain sequence database: Identification of conserved features of primary structure and classification of family members. Methods Enzymol., 1991, 200, 38-62.
[http://dx.doi.org/10.1016/0076-6879(91)00126-H] [PMID: 1956325]
[137]
Taniguchi, Y. The bromodomain and extra-terminal domain (BET) family: Functional anatomy of BET paralogous proteins. Int. J. Mol. Sci., 2016, 17(11), 1849.
[http://dx.doi.org/10.3390/ijms17111849] [PMID: 27827996]
[138]
Padmanabhan, B.; Mathur, S.; Manjula, R.; Tripathi, S. Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases. J. Biosci., 2016, 41(2), 295-311.
[http://dx.doi.org/10.1007/s12038-016-9600-6] [PMID: 27240990]
[139]
Doroshow, D.B.; Eder, J.P.; LoRusso, P.M. BET inhibitors: A novel epigenetic approach. Ann. Oncol., 2017, 28(8), 1776-1787.
[http://dx.doi.org/10.1093/annonc/mdx157] [PMID: 28838216]
[140]
Al-mansour, F.; Alraddadi, A.; He, B.; Saleh, A.; Poblocka, M.; Alzahrani, W.; Cowley, S.; Macip, S. Characterization of the HDAC / PI3K inhibitor CUDC-907 as a novel senolytic. Aging, 2023, 15, 2373-2394.
[141]
Zhang, Y.; Gao, D.; Yuan, Y.; Zheng, R.; Sun, M.; Jia, S.; Liu, J. Cycloastragenol: A novel senolytic agent that induces senescent cell apoptosis and restores physical function in TBI-aged mice. Int. J. Mol. Sci., 2023, 24(7), 6554.
[http://dx.doi.org/10.3390/ijms24076554] [PMID: 37047529]
[142]
Cho, H.J.; Hwang, J.A.; Yang, E.J.; Kim, E.C.; Kim, J.R.; Kim, S.Y.; Kim, Y.Z.; Park, S.C.; Lee, Y.S. Nintedanib induces senolytic effect via STAT3 inhibition. Cell Death Dis., 2022, 13(9), 760.
[http://dx.doi.org/10.1038/s41419-022-05207-8] [PMID: 36055997]
[143]
Sato, S.; Koyama, K.; Ogawa, H.; Murakami, K.; Imakura, T.; Yamashita, Y.; Haji, K. A novel senolytic agent, ARV-825, ameliorates bleomycin-induced pulmonary fibrosis in mice. Am. J. Respir. Crit. Care Med., 2022, 205, A3888.
[144]
Moaddel, R.; Rossi, M.; Rodriguez, S.; Munk, R.; Khadeer, M.; Abdelmohsen, K.; Gorospe, M.; Ferrucci, L. Identification of gingerenone A as a novel senolytic compound. PLoS One, 2022, 17(3), e0266135.
[http://dx.doi.org/10.1371/journal.pone.0266135] [PMID: 35349590]
[145]
Yang, D.; Tian, X.; Ye, Y.; Liang, Y.; Zhao, J.; Wu, T.; Lu, N. Identification of GL-V9 as a novel senolytic agent against senescent breast cancer cells. Life Sci., 2021, 272, 119196.
[http://dx.doi.org/10.1016/j.lfs.2021.119196] [PMID: 33617857]
[146]
Sun, Y. Procyanidin C1 Is a Natural Agent with Senolytic Activity against Aging and Age-Related Diseases. Nat. Metab., 2021.
[147]
Cho, H.J.; Yang, E.J.; Park, J.T.; Kim, J.R.; Kim, E.C.; Jung, K.J.; Park, S.C.; Lee, Y.S. Identification of SYK inhibitor, R406 as a novel senolytic agent. Aging, 2020, 12(9), 8221-8240.
[http://dx.doi.org/10.18632/aging.103135] [PMID: 32379705]
[148]
Ritschka, B.; Knauer-Meyer, T.; Gonçalves, D.S.; Mas, A.; Plassat, J.L.; Durik, M.; Jacobs, H.; Pedone, E.; Di Vicino, U.; Cosma, M.P.; Keyes, W.M. The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice. Genes Dev., 2020, 34(7-8), 489-494.
[http://dx.doi.org/10.1101/gad.332643.119] [PMID: 32139422]
[149]
Salaami, O.; Kuo, C.L.; Drake, M.T.; Kuchel, G.A.; Kirkland, J.L.; Pignolo, R.J. Antidiabetic effects of the senolytic agent dasatinib. Mayo Clin. Proc., 2021, 96(12), 3021-3029.
[http://dx.doi.org/10.1016/j.mayocp.2021.06.025] [PMID: 34772496]
[150]
Kusama, K.; Yamauchi, N.; Yoshida, K.; Azumi, M.; Yoshie, M.; Tamura, K. Senolytic treatment modulates decidualization in human endometrial stromal cells. Biochem. Biophys. Res. Commun., 2021, 571, 174-180.
[http://dx.doi.org/10.1016/j.bbrc.2021.07.075] [PMID: 34330061]
[151]
Novais, E.J.; Tran, V.A.; Johnston, S.N.; Darris, K.R.; Roupas, A.J.; Sessions, G.A.; Shapiro, I.M.; Diekman, B.O.; Risbud, M.V. Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nat. Commun., 2021, 12(1), 5213.
[http://dx.doi.org/10.1038/s41467-021-25453-2] [PMID: 34480023]
[152]
Zhu, Y.; Prata, L.G.P.L.; Gerdes, E.O.W.; Netto, J.M.E.; Pirtskhalava, T.; Giorgadze, N.; Tripathi, U.; Inman, C.L.; Johnson, K.O.; Xue, A.; Palmer, A.K.; Chen, T.; Schaefer, K.; Justice, J.N.; Nambiar, A.M.; Musi, N.; Kritchevsky, S.B.; Chen, J.; Khosla, S.; Jurk, D.; Schafer, M.J.; Tchkonia, T.; Kirkland, J.L. Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans. EBioMedicine, 2022, 77, 103912.
[http://dx.doi.org/10.1016/j.ebiom.2022.103912] [PMID: 35292270]
[153]
Parvizi, M.; Franchi, F.; Arendt, B.K.; Ebtehaj, S.; Rodriguez-Porcel, M.; Lanza, I.R. Senolytic agents lessen the severity of abdominal aortic aneurysm in aged mice. Exp. Gerontol., 2021, 151, 111416.
[http://dx.doi.org/10.1016/j.exger.2021.111416] [PMID: 34022272]
[154]
Justice, J.N.; Nambiar, A.M.; Tchkonia, T.; LeBrasseur, N.K.; Pascual, R.; Hashmi, S.K.; Prata, L.; Masternak, M.M.; Kritchevsky, S.B.; Musi, N.; Kirkland, J.L. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine, 2019, 40, 554-563.
[http://dx.doi.org/10.1016/j.ebiom.2018.12.052] [PMID: 30616998]
[155]
Doolittle, M.L.; Monroe, D.G.; Farr, J.N.; Khosla, S. The role of senolytics in osteoporosis and other skeletal pathologies. Mech. Ageing Dev., 2021, 199, 111565.
[http://dx.doi.org/10.1016/j.mad.2021.111565] [PMID: 34499959]
[156]
Lewinska, A.; Adamczyk-Grochala, J.; Bloniarz, D.; Olszowka, J.; Kulpa-Greszta, M.; Litwinienko, G.; Tomaszewska, A.; Wnuk, M.; Pazik, R. AMPK-mediated senolytic and senostatic activity of quercetin surface functionalized Fe3O4 nanoparticles during oxidant-induced senescence in human fibroblasts. Redox Biol., 2020, 28, 101337.
[http://dx.doi.org/10.1016/j.redox.2019.101337] [PMID: 31622846]
[157]
Liu, Y.; Tang, Z.G.; Lin, Y.; Qu, X.G.; Lv, W.; Wang, G.B.; Li, C.L. Effects of quercetin on proliferation and migration of human glioblastoma U251 cells. Biomed. Pharmacother., 2017, 92, 33-38.
[http://dx.doi.org/10.1016/j.biopha.2017.05.044] [PMID: 28528183]
[158]
Xu, W.; Zhao, T.; Chen, H.; Huang, N.; Gong, H.; Zhang, J.; Yang, Y.; Li, T.; Zhang, G.; Gong, C.; Yang, M.; Xiao, H. Pan-mTOR inhibitors sensitize the senolytic activity of navitoclax via mTORC2 inhibition-mediated apoptotic signaling. Biochem. Pharmacol., 2022, 200, 115045.
[http://dx.doi.org/10.1016/j.bcp.2022.115045] [PMID: 35439535]
[159]
As Sobeai, H.M.; Alohaydib, M.; Alhoshani, A.R.; Alhazzani, K.; Almutairi, M.M.; Saleh, T.; Gewirtz, D.A.; Alotiabi, M.R. Sorafenib, rapamycin, and venetoclax attenuate doxorubicin-induced senescence and promote apoptosis in HCT116 cells. Saudi Pharm. J., 2022, 30(1), 91-101.
[http://dx.doi.org/10.1016/j.jsps.2021.12.004] [PMID: 35145348]
[160]
Estepa-Fernández, A.; García-Fernández, A.; Lérida-Viso, A.; Blandez, J.F.; Galiana, I.; Sancenon-Galarza, F.; Orzáez, M.; Martínez-Máñez, R. Combination of palbociclib with navitoclax based-therapies enhances in vivo antitumoral activity in triple-negative breast cancer. Pharmacol. Res., 2023, 187, 106628.
[http://dx.doi.org/10.1016/j.phrs.2022.106628] [PMID: 36566002]
[161]
Lu, Z.; Zhang, W.; No, Y.J.; Lu, Y.; Mirkhalaf Valashani, S.M.; Rollet, P.; Jiang, L.; Ramaswamy, Y.; Dunstan, C.R.; Jiang, X.; Zreiqat, H. Baghdadite ceramics prevent senescence in human osteoblasts and promote bone regeneration in aged rats. ACS Biomater. Sci. Eng., 2020, 6(12), 6874-6885.
[http://dx.doi.org/10.1021/acsbiomaterials.0c01120] [PMID: 33320606]
[162]
Xing, X.; Huang, H.; Gao, X.; Yang, J.; Tang, Q.; Xu, X.; Wu, Y.; Li, M.; Liang, C.; Tan, L.; Liao, L.; Tian, W. Local elimination of senescent cells promotes bone defect repair during aging. ACS Appl. Mater. Interfaces, 2022, 14(3), 3885-3899.
[http://dx.doi.org/10.1021/acsami.1c22138] [PMID: 35014784]
[163]
Kirkland, J.L.; Tchkonia, T. Senolytic drugs: From discovery to translation. J. Intern. Med., 2020, 288(5), 518-536.
[http://dx.doi.org/10.1111/joim.13141] [PMID: 32686219]
[164]
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.; Wren, J.D.; Niedernhofer, L.J.; Robbins, P.D.; Kirkland, J.L. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell, 2016, 15(3), 428-435.
[http://dx.doi.org/10.1111/acel.12445] [PMID: 26711051]
[165]
Roos, C.M.; Zhang, B.; Palmer, A.K.; Ogrodnik, M.B.; Pirtskhalava, T.; Thalji, N.M.; Hagler, M.; Jurk, D.; Smith, L.A.; Casaclang-Verzosa, G.; Zhu, Y.; Schafer, M.J.; Tchkonia, T.; Kirkland, J.L.; Miller, J.D. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell, 2016, 15(5), 973-977.
[http://dx.doi.org/10.1111/acel.12458] [PMID: 26864908]
[166]
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.; Mazula, D.L.; Brooks, R.W.; Fuhrmann-Stroissnigg, H.; Pirtskhalava, T.; Prakash, Y.S.; Tchkonia, T.; Robbins, P.D.; Aubry, M.C.; Passos, J.F.; Kirkland, J.L.; Tschumperlin, D.J.; Kita, H.; LeBrasseur, N.K. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun., 2017, 8(1), 14532.
[http://dx.doi.org/10.1038/ncomms14532] [PMID: 28230051]
[167]
Palmer, A.K.; Xu, M.; Zhu, Y.; Pirtskhalava, T.; Weivoda, M.M.; Hachfeld, C.M.; Prata, L.G.; van Dijk, T.H.; Verkade, E.; Casaclang-Verzosa, G.; Johnson, K.O.; Cubro, H.; Doornebal, E.J.; Ogrodnik, M.; Jurk, D.; Jensen, M.D.; Chini, E.N.; Miller, J.D.; Matveyenko, A.; Stout, M.B.; Schafer, M.J.; White, T.A.; Hickson, L.J.; Demaria, M.; Garovic, V.; Grande, J.; Arriaga, E.A.; Kuipers, F.; von Zglinicki, T.; LeBrasseur, N.K.; Campisi, J.; Tchkonia, T.; Kirkland, J.L. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell, 2019, 18(3), e12950.
[http://dx.doi.org/10.1111/acel.12950] [PMID: 30907060]
[168]
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.; LeBrasseur, N.K.; Drake, M.T.; Pignolo, R.J.; Pirtskhalava, T.; Tchkonia, T.; Oursler, M.J.; Kirkland, J.L.; Khosla, S. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med., 2017, 23(9), 1072-1079.
[http://dx.doi.org/10.1038/nm.4385] [PMID: 28825716]
[169]
Maher, P. Preventing and treating neurological disorders with the flavonol fisetin. Brain Plast., 2021, 6(2), 155-166.
[http://dx.doi.org/10.3233/BPL-200104] [PMID: 33782648]
[170]
ClinicalTrials.gov is a place to learn about clinical studies from around the world. Available from: https://clinicaltrials.gov/

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy