Trifluridine induces HUVECs senescence by inhibiting mTOR-dependent autophagy.

Abstract

Trifluridine, a key component of trifluridine/tipiracil, is a potential anti-cancer drug that can act effectively on refractory metastatic colorectal cancer. Chemotherapy is important for cancer treatment, but its adverse effects limit its use. Long-term side-effects caused by the drug used during chemotherapy are closely related to the accumulation of cellular senescence. However, the relationship between trifluridine and normal cell aging remains unclear. The purpose of this study is to evaluate whether trifluridine can induce the senescence of human umbilical vein endothelial cells and to explore the possible mechanism. Human umbilical vein endothelial cells were treated with trifluridine, senescence levels were measured via senescence-related acidic β-galactosidase staining and senescence-associated secretory phenotype levels respectively. Autophagy was assessed by the protein levels of LC3II/LC3I and p62, and LC3 fusion was detected by fluorescence microscopy. Chloroquine diphosphate salt and rapamycin were used to detect the effect of trifluridine on autophagy flux and mTOR signaling pathway. Trifluridine increased the expression of senescence-associated acidic β-galactosidase and senescence-related secretory phenotype mRNA levels in cells. In addition, also trifluridine induced cellular senescence by inhibiting autophagy and was closely related to the activation of the mTOR signaling pathway, therefore, we believe that trifluridine may be an effective mTOR activator. The findings also provide a new strategy for establishing autophagy or aging models, as well as a new theoretical basis for the use of trifluridine in clinical treatment.

• Authors: Hui-Jie Jia, Min Zhou, Manoj Kumar Vashisth, Jing Xia, Hui Hua, Qian-Long Dai, Shi-Rui Bai, Qi Zhao, Xiao-Bo Wang, Yi-Ling Shi
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 610 Pg. 119-126 (06 25 2022) ISSN: 1090-2104 [Electronic] United States
• PMID: 35462092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• TOR Serine-Threonine Kinases
• beta-Galactosidase
• Trifluridine

Topics

• Autophagy
• Cellular Senescence
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• TOR Serine-Threonine Kinases (metabolism)
• Trifluridine
• beta-Galactosidase (metabolism)