medigraphic.com

2022, Número 4

<< Anterior Siguiente >>

Rev Educ Bioquimica 2022; 41 (4)


Senolíticos, fármacos para prevenir el deterioro asociado al envejecimiento

Belmont A, Olascoaga-Del Angel KS, Königsberg M

Idioma: Español
Referencias bibliográficas: 45
Paginas: 127-139
Archivo PDF: 369.86 Kb.


RESUMEN

La senescencia celular es una de las características que contribuyen al envejecimiento a nivel celular. Las células senescentes secretan citocinas y quimiocinas que dañan a los tejidos y se han relacionado con el establecimiento de varias patologías asociadas al envejecimiento. Recientemente se ha reportado que el eliminar a las células senescentes de los tejidos disminuye las afectaciones relacionadas con el envejecimiento y mejora la calidad de vida de los animales de experimentación. Lo anterior ha generado una búsqueda por encontrar fármacos o moléculas que eliminen de manera selectiva a las células senescentes y que puedan ser usados en humanos sin generar efectos secundarios. A estas moléculas se les conoce como senolíticos. El objetivo de este artículo es discutir los avances en cuanto a la eliminación de las células senescentes por distintos tipos de senolíticos. Se analizará el reposicionamiento de fármacos para encontrar senolíticos, así como el uso de moléculas provenientes de productos naturales y se discutirán los resultados de los primeros estudios clínicos que actualmente se están realizando con pacientes.


REFERENCIAS (EN ESTE ARTÍCULO)

  1. López-Otín C, Blasco MA, Partridge L, SerranoM, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-217.

  2. Muller M. Cellular Senescence: Molecularmechanisms, In Vivo Significance and RedoxConsiderations. Antioxid. Redox Signal.2009;11:59-98.

  3. Rodier F, Muñoz D, Teachenor R, Chu V, Le O,Bhaumik,D, Coppé J, Campeau E, BeauséjourC, Kim S, Davalos A, Campisi J. DNA-SCARS:distinct nuclear structures that sustaindamage-induced senescence growth arrestand inflammatory cytokine secretion. J CellScien. 2011;124 (1):68-81.

  4. Dimri G. What has senescence got to do withcancer? Cancer Cell. 2005;7:505-512.

  5. López-Diazguerrero NE, López-Araiza H,Conde-Perezprina J, Bucio L, Cárdenas-Aguayo, M, Ventura J, Covarrubias L,Gutiérrez-Ruiz M, Zentella A, Königsberg M.Bcl-2 protects against oxidative stress whileinducing premature senescence. Free Rad.Biol. Med. 2006; 40(7):1161-1169.

  6. Toussaint O, Medrano E, von Zglinicki T.Cellular and molecular mechanisms of stressinducedpremature senescence (SIPS) ofhuman diploid fibroblasts and melanocytes.Exp. Gerontol. 2000;35 (8) 927-945.

  7. Serrano M, Lin AW, McCurrach ME, Beach D,Lowe SW. Oncogenic ras Provokes PrematureCell Senescence Associated with Accumulationof p53 and p16INK4a. Cell. marzo de1997;88(5):593-602.

  8. Torres C, Lewis L, Cristofalo V. Proteasomeinhibitors shorten replicative life span andinduce a senescente-like phenotype of humanfibroblasts. J. Cell Physiol. 2006; 207(:3)845-853.

  9. Fujii S, Hara H, Araya J, Takasaka N, KojimaJ, Ito S, Minagawa S, Yumino Y, Ishikawa T,Numata T, Kawaishi M, Hirano J, Odaka M,Morikawa T, Nishimura S, Nakayama K, KuwanoK. Insufficient autophagy promotes bronchialepithelial cell senescence in chronic obstructivepulmonary disease. OncoImmunology. 2012;1 (5):630-641.

  10. Calcinotto A, Kohli J, Zagato E, Pellegrini L,Demaria M, Alimonti A. Cellular Senescence:Aging, Cancer, and Injury. Physiol Rev. 1 deabril de 2019;99(2):1047-78.

  11. Coppé JP, Desprez PY, Krtolica A, Campisi J(2010) The senescence-associated secretoryphenotype: the dark side of tumor suppression.Annu Rev Pathol 5:99-118.

  12. Lagoumtzi SM, Chondrogianni N. Senolyticsand senomorphics: Natural and synthetictherapeutics in the treatment of aging andchronic diseases. Free Radic Biol Med. agostode 2021;171:169-90.

  13. Zhang L, Pitcher LE, Prahalad V, NiedernhoferLJ, Robbins PD. Targeting cellular senescencewith senotherapeutics: senolyticsand senomorphics. FEBS J. febrero de2022;febs.16350.

  14. Demaria M, Ohtani N, Youssef SA, Rodier F,Toussaint W, Mitchell JR, Laberge RM, Vijg J,Van Steeg H, Dollé ME, Hoeijmakers JH, deBruin A, Hara E, Campisi J. An essential rolefor senescent cells in optimal wound healingthrough secretion of PDGF-AA. Dev Cell.2014;31(6):722-733.

  15. Adams PD. Healing and hurting: molecularmechanisms, functions, and pathologies ofcellular senescence. Mol Cell. 2009;36 (1):2-14.

  16. Storer M, Mas A, Robert-Moreno A, PecoraroM, Ortells MC, Di Giacomo V, Yosef R, PilpelN, Krizhanovsky V, Sharpe J, Keyes WM .Senescence is a developmental mechanismthat contributes to embryonic growth andpatterning. Cell. 2013;155 (5):1119-30.

  17. Muñoz-Espín D, Cañamero M, Maraver A,Gómez-López G, Contreras J, Murillo-CuestaS, Rodríguez-Baeza A, Varela-Nieto I, RuberteJ, Collado M, Serrano M. Programmed cellsenescence during mammalian embryonicdevelopment. Cell. 2013;155 (5):1104-18.

  18. Baker DJ, Wijshake T, Tchkonia T, LeBrasseurNK, Childs BG, van de Sluis B, Kirkland JL, vanDeursen JM. Clearance of p16Ink4a-positivesenescent cells delays ageing-associateddisorders. Nature. 2011;479(7372):232-6.

  19. Demaria M, Ohtani N, Youssef SA, Rodier F,Toussaint W, Mitchell JR, Laberge RM, Vijg J,Van Steeg H, Dollé MET, Hoeijmakers JHJ,de Bruin A, Hara E, Campisi J. An EssentialRole for Senescent Cells in Optimal WoundHealing through Secretion of PDGF-AA. DevCell. 2014;31(6):722-33.

  20. Palmer AK, Xu M, Zhu Y, Pirtskhalava T,Weivoda MM, Hachfeld CM, Prata LG, Dijk TH,Verkade E, Casaclang-Verzosa G, Johnson KO,Cubro H, Doornebal J, Ogrodnik M, Jurk D,Jensen MD, Chini EN, Miller JD, Matveyenko A,Kirkland JL. Targeting senescent cells alleviatesobesity-induced metabolic dysfunction. AgingCell. 2019;18(3):e12950.

  21. Bussian TJ, Aziz A, Meyer CF, Swenson BL,van Deursen JM, Baker DJ. Clearance ofsenescent glial cells prevents tau-dependentpathology and cognitive decline. Nature.2018;562(7728):578-82.

  22. Zhu Y, Tchkonia T, Pirtskhalava T, GowerAC, Ding H, Giorgadze N, Palmer AK, IkenoY, Hubbard GB, Lenburg M, O’Hara SP,LaRusso NF, Miller JD, Roos CM, Verzosa GC,LeBrasseur NK, Wren JD, Farr JN, Khosla S,Kirkland JL. The Achilles’ heel of senescentcells: from transcriptome to senolytic drugs.Aging Cell.2015;14(4):644-58.

  23. Kirkland JL, Tchkonia T, Zhu Y, NiedernhoferLJ, Robbins PD. The Clinical Potential ofSenolytic Drugs. J Am Geriatr Soc. octubrede 2017;65(10):2297-301.

  24. Hickson LJ, Langhi Prata LGP, Bobart SA,Evans TK, Giorgadze N, Hashmi SK, HerrmannSM, Jensen MD, Jia Q, Jordan KL, Kellogg TA,Khosla S, Koerber DM, Lagnado AB, Lawson,DK, LeBrasseur NK, Lerman LO, McDonald KM,McKenzie TJ, Kirkland JL. Senolytics decreasesenescent cells in humans: Preliminary reportfrom a clinical trial of Dasatinib plus Quercetinin individuals with diabetic kidney disease.EBioMedicine. 2019;47:446-56.

  25. Xu M, Pirtskhalava T, Farr JN, Weigand BM,Palmer AK, Weivoda MM, Inman CL, OgrodnikMB, Hachfeld CM, Fraser DG, Onken JL,Johnson KO, Verzosa GC, Langhi LGP, WeiglM, Giorgadze N, LeBrasseur NK, Miller JD, JurkD, Kirkland JL. Senolytics improve physicalfunction and increase lifespan in old age. NatMed. 2018;24(8):1246-56.

  26. Wishart DS, Feunang YD, Guo AC, Lo EJ, MarcuA, Grant JR, Sajed T, Johnson D, Li C, SayeedaZ, Assempour N, Iynkkaran I, Liu Y, MaciejewskiA, Gale N, Wilson A, Chin L, Cummings R, LeD, Wilson M. DrugBank 5.0: a major updateto the DrugBank database for 2018. NucleicAcids Res. 2018;46(D1):D1074-82.

  27. Yosef R, Pilpel N, Tokarsky-Amiel R, Biran A,Ovadya Y, Cohen S, Vadai E, Dassa L, ShaharE, Condiotti R, Ben-Porath I, KrizhanovskyV. Directed elimination of senescent cells byinhibition of BCL-W and BCL-XL. Nat Commun.2016;7:11190.

  28. Colucci M, Revandkar A, Alimonti, A (2020)New ALK inhibitor senolytic drugs (fondazioneper l’istituto oncologico di ricercar) Patent.

  29. Cho SH, Chen JA, Sayed F, Ward ME, Gao F,Nguyen TA, Krabbe G, Sohn PD, Lo I, MinamiS, Devidze N, Zhou Y, Coppola G, Gan L. SIRT1deficiency in microglia contributes to cognitivedecline in aging and neurodegeneration viaepigenetic regulation of IL-1β. J Neurosci OffJ Soc Neurosci. 2015;35(2):807-18.

  30. Fuhrmann-Stroissnigg H, Ling YY, Zhao J,McGowan SJ, Zhu Y, Brooks RW, Rassi D,Gregg SQ, Stripay JL, Dorronsoro A, CorboL, Tang P, Bukata C, Ring N, Giacca M, LiX, Tchkonia T, Kirkland JL, Niedernhofer LJ,Robbins PD. Identification of HSP90 inhibitorsas a novel class of senolytics. Nat Commun.2017;8(1):422.

  31. Tse C, Shoemaker AR, Adickes J, AndersonMG, Chen J, Jin S, Johnson,EF, Marsh KC,Mitten MJ, Nimmer P, Roberts L, Tahir SK,Xiao Y, Yang X, Zhang H, Fesik S, RosenbergSH, Elmore SW. ABT-263: A Potent and OrallyBioavailable Bcl-2 Family Inhibitor. CancerRes. 2008;68(9):3421-8.

  32. Ozsvari B, Nuttall JR, Sotgia F, Lisanti MP.Azithromycin and Roxithromycin definea new family of «senolytic» drugs thattarget senescent human fibroblasts. Aging.2018;10(11):3294-307.

  33. Triana-Martínez F, Picallos-Rabina P, DaSilva-Álvarez S, Pietrocola F, Llanos S,Rodilla V, Soprano E, Pedrosa P, Ferreirós A,Barradas M, Hernández-González F, LalindeM, Prats N, Bernadó C, González P, GómezM, Ikonomopoulou MP, Fernández-Marcos PJ,García-Caballero T, Collado M. Identificationand characterization of Cardiac Glycosidesas senolytic compounds. Nat Commun.2019;10(1):4731.

  34. Rosas-González VC, Téllez-Bañuelos MC,Hernández-Flores G, Bravo-Cuellar A, Aguilar-Lemarroy A, Jave-Suárez LF, et al. Differentialeffects of alliin and allicin on apoptosis andsenescence in luminal A and triple-negativebreast cancer: Caspase, ΔΨm, and proapoptoticgene involvement. Fundam ClinPharmacol. 2020;34(6):671-86.

  35. Dörr JR, Yu Y, Milanovic M, Beuster G,Zasada C, Däbritz JHM, et al. Synthetic lethalmetabolic targeting of cellular senescence incancer therapy. Nature. 2013;501(7467):421-5.

  36. Liu X, Wang Y, Zhang X, Gao Z, Zhang S, ShiP, Zhang X, Song L, Hendrickson H, Zhou D,Zheng G. Senolytic activity of piperlongumineanalogues: Synthesis and biological evaluation.Bioorg Med Chem. 2018;26(14):3925-38.

  37. Yang D, Tian X, Ye Y, Liang Y, Zhao J, Wu T, LuN. Identification of GL-V9 as a novel senolyticagent against senescent breast cancer cells.Life Sci. 2021;272:119196.

  38. Li W, He Y, Zhang R, Zheng G, Zhou D. Thecurcumin analog EF24 is a novel senolyticagent. Aging. 2019;11(2):771-82.

  39. Zhu Y, Doornebal EJ, Pirtskhalava T, GiorgadzeN, Wentworth M, Fuhrmann-Stroissnigg H,Niedernhofer LJ, Robbins PD, Tchkonia T,Kirkland JL. New agents that target senescentcells: the flavone, fisetin, and the BCL-XLinhibitors, A1331852 and A1155463. Aging.2017;9(3):955-63.

  40. Cho HJ, Yang EJ, Park JT, Kim JR, Kim EC,Jung KJ, et al. Identification of SYK inhibitor,R406 as a novel senolytic agent. Aging.2020;12(9):8221-40.

  41. Cherif H, Bisson DG, Mannarino M, Rabau O,Ouellet JA, Haglund L. Senotherapeutic drugsfor human intervertebral disc degenerationand low back pain. eLife. 2020;9:e54693.

  42. Justice JN, Nambiar AM, Tchkonia T, LeBrasseurNK, Pascual R, Hashmi SK, Prata L, MasternakMM, Kritchevsky SB, Musi N, Kirkland JL.Senolytics in idiopathic pulmonary fibrosis:Results from a first-in-human, open-label, pilotstudy. EBioMedicine. 2019;40:554-63.

  43. El-Nimri NW, Moore SM, Zangwill LM, ProudfootJA, Weinreb RN, Skowronska-Krawczyk D,Baxter SL. Evaluating the neuroprotectiveimpact of senolytic drugs on human vision.Sci Rep. 2020;10 (1):21752.

  44. Clinicaltrials.gov. 2022. Disponible en https://clinicaltrials.gov/

  45. Olascoaga-Del Angel KS, Gutierrez H,Königsberg M, Pérez-Villanueva J, López-Diazguerrero NE. Exploring the fuzzy borderbetween senolytics and senomorphics withchemoinformatics and systems pharmacology.Biogerontology. 2022;23(4):453-71.




2020     |     www.medigraphic.com