Targeting senescent cells in translational medicine

被引:219
作者
Paez-Ribes, Marta [1 ]
Gonzalez-Gualda, Estela [1 ]
Doherty, Gary J. [2 ]
Munoz-Espin, Daniel [1 ]
机构
[1] Univ Cambridge, Dept Oncol, CRUK Cambridge Ctr Early Detect Programme, Hutchison MRC Res Ctr, Cambridge, England
[2] Cambridge Univ Hosp NHS Fdn Trust, Dept Oncol, Cambridge Biomed Campus, Cambridge, England
基金
英国医学研究理事会;
关键词
age-related disorders; cellular senescence; SASP; senolytic drugs; senoprobes; ACTIVATED STELLATE CELLS; CELLULAR SENESCENCE; SECRETORY PHENOTYPE; BETA-GALACTOSIDASE; DNA-DAMAGE; FLUORESCENT-PROBE; BCL-2; FAMILY; CANCER; INHIBITORS; COMBINATION;
D O I
10.15252/emmm.201810234
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Organismal ageing is a complex process driving progressive impairment of functionality and regenerative potential of tissues. Cellular senescence is a state of stable cell cycle arrest occurring in response to damage and stress and is considered a hallmark of ageing. Senescent cells accumulate in multiple organs during ageing, contribute to tissue dysfunction and give rise to pathological manifestations. Senescence is therefore a defining feature of a variety of human age-related disorders, including cancer, and targeted elimination of these cells has recently emerged as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration. In addition, in vivo identification of senescent cells has significant potential for early diagnosis of multiple pathologies. Here, we review existing senolytics, small molecules and drug delivery tools used in preclinical therapeutic strategies involving cellular senescence, as well as probes to trace senescent cells. We also review the clinical research landscape in senescence and discuss how identifying and targeting cellular senescence might positively affect pathological and ageing processes.
引用
收藏
页数:19
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共 134 条
[21]   Senescent intimal foam cells are deleterious at all stages of atherosclerosis [J].
Childs, Bennett G. ;
Baker, Darren J. ;
Wijshake, Tobias ;
Conover, Cheryl A. ;
Campisi, Judith ;
van Deursen, Jan M. .
SCIENCE, 2016, 354 (6311) :472-477
[22]   Senescence and apoptosis: dueling or complementary cell fates? [J].
Childs, Bennett G. ;
Baker, Darren J. ;
Kirkland, James L. ;
Campisi, Judith ;
van Deursen, Jan M. .
EMBO REPORTS, 2014, 15 (11) :1139-1153
[23]   A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors [J].
Cleary, James M. ;
Lima, Caio Max S. Rocha ;
Hurwitz, Herbert I. ;
Montero, Alberto J. ;
Franklin, Catherine ;
Yang, Jianning ;
Graham, Alison ;
Busman, Todd ;
Mabry, Mack ;
Holen, Kyle ;
Shapiro, Geoffrey I. ;
Uronis, Hope .
INVESTIGATIONAL NEW DRUGS, 2014, 32 (05) :937-945
[24]   Tumour biology -: Senescence in premalignant tumours [J].
Collado, M ;
Gil, J ;
Efeyan, A ;
Guerra, C ;
Schuhmacher, AJ ;
Barradas, M ;
Benguría, A ;
Zaballos, A ;
Flores, JM ;
Barbacid, M ;
Beach, D ;
Serrano, M .
NATURE, 2005, 436 (7051) :642-642
[25]   SENESCENCE Senescence in tumours: evidence from mice and humans [J].
Collado, Manuel ;
Serrano, Manuel .
NATURE REVIEWS CANCER, 2010, 10 (01) :51-57
[26]   Tumor Suppressor and Aging Biomarker p16INK4a Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype [J].
Coppe, Jean-Philippe ;
Rodier, Francis ;
Patil, Christopher K. ;
Freund, Adam ;
Desprez, Pierre-Yves ;
Campisi, Judith .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (42) :36396-36403
[27]   Protocols to detect senescence-associated beta-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo [J].
Debacq-Chainiaux, Florence ;
Erusalimsky, Jorge D. ;
Campisi, Judith ;
Toussaint, Olivier .
NATURE PROTOCOLS, 2009, 4 (12) :1798-1806
[28]   Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse [J].
Demaria, Marco ;
O'Leary, Monique N. ;
Chang, Jianhui ;
Shao, Lijian ;
Liu, Su ;
Alimirah, Fatouma ;
Koenig, Kristin ;
Le, Catherine ;
Mitin, Natalia ;
Deal, Allison M. ;
Alston, Shani ;
Academia, Emmeline C. ;
Kilmarx, Sumner ;
Valdovinos, Alexis ;
Wang, Boshi ;
de Bruin, Alain ;
Kennedy, Brian K. ;
Melov, Simon ;
Zhou, Daohong ;
Sharpless, Norman E. ;
Muss, Hyman ;
Campisi, Judith .
CANCER DISCOVERY, 2017, 7 (02) :165-176
[29]   An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA [J].
Demaria, Marco ;
Ohtani, Naoko ;
Youssef, Sameh A. ;
Rodier, Francis ;
Toussaint, Wendy ;
Mitchell, James R. ;
Laberge, Remi-Martin ;
Vijg, Jan ;
Van Steeg, Harry ;
Dolle, Martijn E. T. ;
Hoeijmakers, Jan H. J. ;
de Bruin, Alain ;
Hara, Eiji ;
Campisi, Judith .
DEVELOPMENTAL CELL, 2014, 31 (06) :722-733
[30]   Double-edged swords as cancer therapeutics: simultaneously targeting p53 and NF-κB pathways [J].
Dey, Anwesha ;
Tergaonkar, Vinay ;
Lane, David P. .
NATURE REVIEWS DRUG DISCOVERY, 2008, 7 (12) :1031-1040