Metformin mitigates SASP secretion and LPS-triggered hyper-inflammation in Doxorubicin-induced senescent endothelial cells

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.

Senolytic treatment alleviates doxorubicin‐induced chemobrain

“…There were several similarities in the periphery and the brain, between Dox treatment and aging, which were ameliorated by ABT‐263 treatment. Dox treatment‐induced gene markers of cellular senescence in peripheral tissues ( Cdkn2a , Cdkn1a , IL‐6 , Mmp3 , Tnfsf11 ) (Abdelgawad et al., 2023 ; Lopez‐Dominguez et al., 2021 ; Sun et al., 2022 ) and, similar to aging, these markers were reduced by senolytic treatment (Budamagunta et al., 2023 ). Furthermore, Dox treatment increased systemic cytokines/chemokines, which were reduced by ABT‐263 treatment.…”

“…The mechanisms for chemobrain include induction of cellular senescence, increased oxidative stress, and inflammation (Cardoso et al., 2020 ; Chen et al., 2007 ; Conklin, 2004 ; Gibson et al., 2019 ; Hurria et al., 2016 ; Hutchinson et al., 2012 ; Vyas et al., 2014 ; Wang et al., 2015 ). Chemotherapeutic agents like doxorubicin (Dox) have been employed as a model of aging and age‐related cognitive decline (Abdelgawad et al., 2023 ; Bagnall‐Moreau et al., 2019 ; Sun et al., 2022 ).…”

Vascular Aging: Assessment and Intervention

“…It also improves age-related vascular function significantly. 159 It has been reported in the REMOVAL trial that the age-related carotid IMT increase was reversed with a 0.012mm/year reduction in diabetic patients treated with metformin for 5 years. 160 The percentage changes in coronary blood flow in response to acetylcholine were increased by 75% after 6 weeks of metformin treatment in pre-diabetic patients compared with the non-treated group.…”

Accelerated Aging in Cancer Survivors: Cellular Senescence, Frailty, and Possible Opportunities for Interventions

“…Senomorphics include rapamycin, metformin, resveratrol, and aspirin [ 77 ]. In a recently published study of chemotherapy-induced senescent endothelial cells, the group treated with metformin had lower levels of SASP factors compared to the group without metformin treatment [ 87 ]. Multiple clinical trials that aim to evaluate the impact of the clearance of senescence in cancer survivors are currently in the recruiting phase.…”