Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation.
Angiogenesis Inhibitors
/ pharmacology
Antineoplastic Agents
/ administration & dosage
Antioxidants
/ pharmacology
Ataxia Telangiectasia Mutated Proteins
/ metabolism
Axitinib
/ pharmacology
Cellular Senescence
/ drug effects
Endothelial Cells
/ drug effects
Enzyme Activation
Human Umbilical Vein Endothelial Cells
Humans
Neovascularization, Pathologic
/ prevention & control
Protein Kinase Inhibitors
/ administration & dosage
Reactive Oxygen Species
/ metabolism
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
12
10
2018
accepted:
15
03
2019
revised:
15
02
2019
pubmed:
11
4
2019
medline:
15
2
2020
entrez:
11
4
2019
Statut:
ppublish
Résumé
Inhibitors of Vascular Endothelial Growth Factor target both tumor vasculature and cancer cells that have hijacked VEGF Receptors (VEGFRs) signaling for tumor growth-promoting activities. It is important to get precise insight in the specificity of cell responses to these antiangiogenic drugs to maximize their efficiency and minimize off-target systemic toxicity. Here we report that Axitinib, an inhibitor of VEGFRs currently in use as a second line treatment for advanced renal cell carcinoma, promotes senescence of human endothelial cells in vitro. A one-hour pulse of Axitinib is sufficient for triggering cell senescence. Mechanistically, this requires oxidative stress-dependent activation of the Ataxia Telangiectasia Mutated (ATM) kinase. Axitinib-mediated senescence promoting action is prevented by short-term treatment with antioxidants or ATM inhibitors, which conversely fail to prevent senescence induced by the DNA-damaging drug doxorubicin. Coherently, induction of oxidative stress-related genes distinguishes the response of endothelial cells to Axitinib from that to doxorubicin. Importantly, an Axitinib pulse causes cell senescence in glioblastoma cells. However, neither antioxidants nor ATM inhibitors can reverse this phenotype. Thus, antioxidants may selectively protect endothelial cells from Axitinib by decreasing systemic toxicity and maintaining a functional vascularization necessary for efficient delivery of chemotherapeutic drugs within the tumor mass.
Identifiants
pubmed: 30967634
doi: 10.1038/s41388-019-0798-2
pii: 10.1038/s41388-019-0798-2
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Antineoplastic Agents
0
Antioxidants
0
Protein Kinase Inhibitors
0
Reactive Oxygen Species
0
Axitinib
C9LVQ0YUXG
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5413-5424Références
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