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Cardiac glycosides are broad-spectrum senolytics.

ABSTRACT: Senescence is a cellular stress response that results in the stable arrest of old, damaged or preneoplastic cells. Oncogene-induced senescence is tumor suppressive but can also exacerbate tumorigenesis through the secretion of pro-inflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed senolytics, have proved beneficial in animal models of many age-associated diseases. Here, 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 pro-apoptotic Bcl2-family protein NOXA. We show that cardiac glycosides synergize with anti-cancer drugs to kill tumor cells and eliminate senescent cells that accumulate after irradiation or in old mice. Ouabain also eliminates senescent preneoplastic cells. Our findings suggest that cardiac glycosides may be effective anti-cancer drugs by acting through multiple mechanism. Given the broad range of senescent cells targeted by cardiac glycosides their use against age-related diseases warrants further exploration.

SUBMITTER: Guerrero A

PROVIDER: S-EPMC6887543 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Cardiac glycosides are broad-spectrum senolytics.

Guerrero Ana A Herranz Nicolás N Sun Bin B Wagner Verena V Gallage Suchira S Guiho Romain R Wolter Katharina K Pombo Joaquim J Irvine Elaine E EE Innes Andrew J AJ Birch Jodie J Glegola Justyna J Manshaei Saba S Heide Danijela D Dharmalingam Gopuraja G Harbig Jule J Olona Antoni A Behmoaras Jacques J Dauch Daniel D Uren Anthony G AG Zender Lars L Vernia Santiago S Martínez-Barbera Juan Pedro JP Heikenwalder Mathias M Withers Dominic J DJ Gil Jesús J

Nature metabolism 20191021 11

Senescence is a cellular stress response that results in the stable arrest of old, damaged or preneoplastic cells. Oncogene-induced senescence is tumor suppressive but can also exacerbate tumorigenesis through the secretion of pro-inflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed senolytics, have proved beneficial in animal models of many age-associated diseases. Here, we show that the cardiac glycoside, ouabain, is a senolytic agent with broad activi ...[more]

PMID: 31799499

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Project description:The phagocytic clearance of apoptotic cells, termed efferocytosis, is essential for both tissue homeostasis and tissue health during cell death-inducing treatments. Failure to efficiently clear apoptotic cells augment the risk of pathological inflammation and has been linked to a myriad of autoimmune and inflammatory diseases. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Interestingly, clinical evidence suggests that prolonged use of broad-spectrum antibiotics is associated with an increased risk of autoimmune and inflammatory disease development. We therefore hypothesized that intestinal microbes produce molecular signals that regulate efferocytotic ability in tissue phagocytes beyond the intestines. Here, we find that macrophages, the body’s professional phagocyte, display impaired efferocytosis in the peritoneum of broad-spectrum antibiotics (ABX)-treated, vancomycin-treated, and germ-free mice in vivo, the latter of which could be rescued by fecal microbiota transplantation. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosted efferocytosis efficiency and capacity in mouse and human macrophages, with both intestinal and local delivery of butyrate capable of rescuing ABX-induced large peritoneal macrophage (LPM) efferocytosis defects. Bulk mRNA sequencing of butyrate-treated primary macrophages in vitro and single cell mRNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice revealed specific regulation of efferocytosis-supportive transcriptional programs. Specifically, we found that the efferocytosis receptor T-cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) was downregulated in LPMs of ABX-treated mice which was rescued by oral butyrate and that TIM-4 was required for the butyrate-induced enhancement of LPM efferocytosis capacity in vivo. Strikingly, LPM efferocytosis was impaired well-beyond withdrawal of ABX and, importantly, ABX-treated mice exhibited significantly worse disease in a mouse model of system lupus erythematosus. Collectively, our results demonstrate that homeostatic efferocytosis relies on distal molecular signals and suggest that a defect in homeostatic efferocytosis may contribute to the clinically observed link between broad-spectrum antibiotics use and inflammatory disease.

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Cardiac glycosides are broad-spectrum senolytics.

Publications

Cardiac glycosides are broad-spectrum senolytics.

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