EA.hy926 Cells and HUVECs Share Similar Senescence Phenotypes but Respond Differently to the Senolytic Drug ABT-263

Abstract

Doxorubicin (DOX) induces endothelial cell (EC) senescence, which contributes to endothelial dysfunction and cardiovascular complications. Senolytic drugs selectively eliminate senescent cells to ameliorate senescence-mediated pathologies. Previous studies have demonstrated differences between immortalized and primary EC models in some characteristics. However, the response of DOX-induced senescent ECs to senolytics has not been determined across these two models. In the present work, we first established a comparative characterization of DOX-induced senescence phenotypes in immortalized EA.hy926 endothelial-derived cells and primary human umbilical vein EC (HUVECs). Thereafter, we evaluated the senolytic activity of four senolytics across both ECs. Following the DOX treatment, both EA.hy926 and HUVECs shared similar senescence phenotypes characterized by upregulated senescence markers, increased SA-β-gal activity, cell cycle arrest, and elevated expression of the senescence-associated secretory phenotype (SASP). The potentially senolytic drugs dasatinib, quercetin, and fisetin demonstrated a lack of selectivity against DOX-induced senescent EA.hy926 cells and HUVECs. However, ABT-263 (Navitoclax) selectively induced the apoptosis of DOX-induced senescent HUVECs but not EA.hy926 cells. Mechanistically, DOX-treated EA.hy926 cells and HUVECs demonstrated differential expression levels of the BCL-2 family proteins. In conclusion, both EA.hy926 cells and HUVECs demonstrate similar DOX-induced senescence phenotypes but they respond differently to ABT-263, presumably due to the different expression levels of BCL-2 family proteins.

The Potential of Senescence as a Target for Developing Anticancer Therapy

“…Senolytic drugs, such as dasatinib, quercetin, and fisetin, eliminated doxorubicin-induced senescent cells by inducing apoptosis [ 30 ]. Doxorubicin increased the expression of the SASP to induce senescence in endothelial cells [ 30 ].…”

“…Senolytic drugs, such as dasatinib, quercetin, and fisetin, eliminated doxorubicin-induced senescent cells by inducing apoptosis [ 30 ]. Doxorubicin increased the expression of the SASP to induce senescence in endothelial cells [ 30 ]. Dasatinib and quercetin attenuated cisplatin-induced ovarian injury by targeting senescent cells and reducing DNA damage in primary granulosa cells [ 171 ].…”

“…This implies the role of senescence in anticancer drug resistance. Doxorubicin (DOX) induced endothelial cell (EC) senescence based on SA-β-gal activity, the upregulation of senescence markers (p53, p21, and cyclinD1), and the elevated expression of SASP [ 30 ].…”

Size-Dependent Polymeric Nanoparticle Distribution in a Static versus Dynamic Microfluidic Blood Vessel Model: Implications for Nanoparticle-Based Drug Delivery

“…The EA.hy926 cell line was selected because it is well-established and widely used in the field of endothelial cell biology . Additionally, it has been shown that it retains many of the physiological features of primary endothelial cells, which makes it a suitable model for investigating vascular function. , …”

Anthracycline-induced cardiotoxicity and senescence

“…Although Lérida-Viso et al showed that navitoclax treatment reduced myocardial senescence, they did not investigate which senescent cell lineages were reduced by treatment. However, navitoclax has demonstrated in vitro senolytic activity in multiple myocardial-resident cell lineages, including cardiomyocytes and primary endothelial cells ( Anderson et al, 2019 ; Abdelgawad et al, 2022a ), and in the context of other disease models, senolytics have shown the potential to eliminate cell populations including cardiomyocytes, fibroblasts, endothelial cells, and even lymphocytes, all of which have roles in pathological myocardial remodeling ( Childs et al, 2016 ; Dookun et al, 2020 ; Martin-Ruiz et al, 2020 ). Furthermore, in the context of aging and cardiac ischemia-reperfusion, navitoclax mediates the elimination of both cardiomyocyte and non-cardiomyocyte senescent populations and attenuates inflammation and myocardial remodeling, reducing both fibrosis and hypertrophy ( Anderson et al, 2019 ; Walaszczyk et al, 2019 ; Dookun et al, 2020 ).…”