5‐fluorouracil causes endothelial cell senescence: potential protective role of glucagon‐like peptide 1

Abstract

BACKGROUND AND PURPOSE5-fluorouracil (5FU) and its prodrug, capecitabine, can damage endothelial cells, whilst endothelial integrity is preserved by glucagon-like peptide 1 (GLP-1). Here, we studied the effect of 5FU on endothelial senescence and whether GLP-1 antagonizes it. EXPERIMENTAL APPROACHEA.hy926 cells were exposed to 5FU or sera from patients taking capecitabine, with or without pre-incubation with GLP-1. Senescence was identified by expression of senescence-associated β-galactosidase and p16INK4a and reduced cell proliferation. Soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and CD146 (marker of endothelial injury) were measured by ELISA before and at completion of capecitabine chemotherapy. RT-PCR, western blotting, functional experiments with signalling inhibitors and ERK1/2 silencing were performed to characterize 5FU-induced phenotype and elucidate the pathways underlying 5FU and GLP-1 activity. KEY RESULTSBoth 5FU and sera from capecitabine-treated patients stimulated endothelial cell senescence. 5FU-elicited senescence occurred via activation of p38 and JNK, and was associated with decreased eNOS and SIRT-1 levels. Furthermore, 5FU up-regulated VCAM1 and TYMP (encodes enzyme activating capecitabine and 5FU), and sVCAM-1 and CD146 concentrations were higher after than before capecitabine chemotherapy. A non-significant trend for higher ICAM1 levels was also observed. GLP-1 counteracted 5FU-initiated senescence and reduced eNOS and SIRT-1 expression, this protection being mediated by GLP-1 receptor, ERK1/2 and, possibly, PKA and PI3K. CONCLUSIONS AND IMPLICATIONS5FU causes endothelial cell senescence and dysfunction, which may contribute to its cardiovascular side effects. 5FU-triggered senescence was prevented by GLP-1, raising the possibility of using GLP-1 analogues and degradation inhibitors to treat 5FU and capecitabine vascular toxicity.

Angelica sinensis Polysaccharides Ameliorate Stress-Induced Premature Senescence of Hematopoietic Cell via Protecting Bone Marrow Stromal Cells from Oxidative Injuries Caused by 5-Fluorouracil

“…In our study, 5-FU caused HS-5 cell cycle arrest in G1 phase ( Figure 2 c,d) and a significant rise in apoptosis ( Figure 2 e,f), suggesting that apoptosis is a response for HS-5 stromal cells to 5-FU treatment the same as cancer cells respond to 5-FU. Moreover, although a very small number of documents suggest that senescence is also another cellular response to 5-FU [ 84 ], using senescence-specific SA-β-gal staining, a classical index for cellular senescence, we found an increase in positive ratio after 5-FU treatment ( Figure 2 g,h), suggesting that, apart from apoptosis, some survival HS-5 cells underwent senescence with permanent cell cycle arrest. Encouragingly, we found that ASP alleviated stress in HS-5 cell caused by 5-FU treatment.…”

Antineoplastic Drug-Induced Cardiotoxicity: A Redox Perspective

“…Silent ischemia due to cardiac stress test has been reported in 6–7% of 5-FU-treated patients (Lestuzzi et al, 2014 ). The mechanisms involved in the CTX of 5-FU and its metabolites involve inhibition of NO (Cianci et al, 2003 ; Shoemaker et al, 2004 ), enhanced generation of ROS/RNS (Lamberti et al, 2014 ), higher endothelial thrombogenicity (Kalam and Marwick, 2013 ) and senescence (Altieri et al, 2017 ), and DNA and RNA damage. 5-FU can induce oxidative stress in cardiomyocytes and endothelial cells.…”

Untitled

“…Cardiotoxicity: Among all antimetabolites, 5-FU is most extensively studied drugs in term of cardiotoxicity 37 . It has a direct effect on myocardial cells and on endothelial cells 38 . Mononuclear inflammations and myocardial necrosis have been observed in a patient who died from myocardial infarction followed by 5-FU therapy 39 .…”