Abstract
Introduction: Doxorubicin (DOX), a chemotherapeutic drug, induces senescence and increases the secretion of senescence-associated secretory phenotype (SASP) in endothelial cells (ECs), which contributes to DOX-induced inflammaging. Metformin, an anti-diabetic drug, demonstrates senomorphic effects on different models of senescence. However, the effects of metformin on DOX-induced endothelial senescence have not been reported before. Senescent ECs exhibit a hyper-inflammatory response to lipopolysachharide (LPS). Therefore, in our current work, we identified the effects of metformin on DOX-induced endothelial senescence and LPS-induced hyper-inflammation in senescent ECs. Methods: ECs were treated with DOX ± metformin for 24 h followed by 72 h incubation without DOX to establish senescence. Effects of metformin on senescence markers expression, SA-β-gal activity, and SASP secretion were assessed. To delineate the molecular mechanisms, the effects of metformin on major signaling pathways were determined. The effect of LPS ± metformin was determined by stimulating both senescent and non-senescent ECs with LPS for an additional 24 h. Results: Metformin corrected DOX-induced upregulation of senescence markers and decreased the secretion of SASP factors and adhesion molecules. These effects were associated with a significant inhibition of the JNK and NF-κB pathway. A significant hyper-inflammatory response to LPS was observed in DOX-induced senescent ECs compared to non-senescent ECs. Metformin blunted LPS-induced upregulation of pro-inflammatory SASP factors. Conclusion: Our study demonstrates that metformin mitigates DOX-induced endothelial senescence phenotype and ameliorates the hyper-inflammatory response to LPS. These findings suggest that metformin may protect against DOX-induced vascular aging and endothelial dysfunction and ameliorate infection-induced hyper-inflammation in DOX-treated cancer survivors.
| Original language | English (US) |
|---|---|
| Article number | 1170434 |
| Journal | Frontiers in Aging |
| Volume | 4 |
| DOIs | |
| State | Published - 2023 |
Bibliographical note
Funding Information:This research is supported by the National Heart, Lung, and Blood Institute, grant R01HL151740. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. IA is supported by the Doctoral Dissertation Fellowship (DDF) offered by the University of Minnesota and the Bighley Graduate Fellowship from the College of Pharmacy. KA is supported by the NIH T32 Training Grant “Functional Proteomics of 249 Aging” (FPATG) 5T32AG029796-14 (MPI).
Publisher Copyright:
Copyright © 2023 Abdelgawad, Agostinucci, Sadaf, Grant and Zordoky.
Keywords
- LPS
- SASP
- doxorubicin
- endothelial senescence
- metformin
- senomorphics
PubMed: MeSH publication types
- Journal Article
