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Cardiac glycosides are broad-spectrum senolytics

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Title: Cardiac glycosides are broad-spectrum senolytics
Authors: Guerrero, A
Herranz, N
Sun, B
Wagner, V
Gallage, S
Guiho, R
Wolter, K
Pombo, J
Irvine, EE
Innes, AJ
Birch, J
Glegola, J
Manshaei, S
Heide, D
Dharmalingam, G
Harbig, J
Olona, A
Behmoaras, J
Dauch, D
Uren, AG
Zender, L
Vernia, S
Martínez-Barbera, JP
Heikenwalder, M
Withers, DJ
Gil, J
Item Type: Journal Article
Abstract: Senescence is a cellular stress response that results in the stable arrest of old, damaged or pre-neoplastic cells. Oncogene-induced senescence is tumour suppressive but can also exacerbate tumorigenesis through the secretion of proinflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed ‘senolytics’, have proved beneficial in animal models of many age-associated diseases. In the present study, we show that the cardiac glycoside ouabain is a senolytic agent with broad activity. Senescent cells are sensitized to ouabain-induced apoptosis, a process mediated in part by induction of the proapoptotic Bcl-2 family protein NOXA. We demonstrate that cardiac glycosides synergize with anti-cancer drugs to kill tumour cells and eliminate senescent cells that accumulate after irradiation or in old mice. Ouabain also eliminates senescent pre-neoplastic cells. The findings of the present study suggest that cardiac glycosides may be effective anti-cancer drugs by acting through multiple mechanisms. Given the broad range of senescent cells targeted by cardiac glycosides, their use against age-related diseases warrants further exploration.
Issue Date: 21-Oct-2019
Date of Acceptance: 10-Sep-2019
URI: http://hdl.handle.net/10044/1/74224
DOI: 10.1038/s42255-019-0122-z
ISSN: 2522-5812
Publisher: Nature Research
Start Page: 1074
End Page: 1088
Journal / Book Title: Nature Metabolism
Volume: 1
Issue: 10
Copyright Statement: © 2019 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1038/s42255-019-0122-z.
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Wellcome Trust
Medical Research Council
Funder's Grant Number: MR/M004716/1
MR/N01121X/1
511377
MC-A654-5QB40
Keywords: Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
CELLULAR SENESCENCE
SECRETORY PHENOTYPE
CELLS
MECHANISMS
CONTRIBUTES
CLEARANCE
PROGRAM
PHARMACOKINETICS
CHEMOTHERAPY
RESISTANCE
Animals
Antineoplastic Agents
Apoptosis
Cardiac Glycosides
Cellular Senescence
Humans
Mice
Ouabain
Quercetin
Rats
Animals
Humans
Mice
Rats
Quercetin
Ouabain
Cardiac Glycosides
Antineoplastic Agents
Apoptosis
Cellular Senescence
Publication Status: Published
Online Publication Date: 2019-10-21
Appears in Collections:Department of Immunology and Inflammation
Institute of Clinical Sciences
Faculty of Medicine