Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation

Area of Science:

• Oncology
• Cell Biology
• Pharmacology

Background:

• Vascular Endothelial Growth Factor (VEGF) inhibitors target tumor vasculature and cancer cells.
• Understanding cell-specific responses to antiangiogenic drugs is crucial for efficacy and minimizing toxicity.
• Axitinib is a VEGFR inhibitor used for advanced renal cell carcinoma.

Purpose of the Study:

• To investigate the precise mechanism of Axitinib-induced endothelial cell senescence.
• To determine the role of oxidative stress and ATM kinase in Axitinib's effects.
• To explore the potential of antioxidants and ATM inhibitors in modulating Axitinib's action.

Main Methods:

• In vitro treatment of human endothelial cells and glioblastoma cells with Axitinib.
• Assessment of cell senescence induction.
• Evaluation of oxidative stress markers and ATM kinase activation.
• Treatment with antioxidants and ATM inhibitors.

Main Results:

• A short pulse of Axitinib induces senescence in human endothelial cells.
• This senescence is dependent on oxidative stress and Ataxia Telangiectasia Mutated (ATM) kinase activation.
• Antioxidants or ATM inhibitors prevent Axitinib-induced endothelial cell senescence but not doxorubicin-induced senescence.
• Axitinib also induces senescence in glioblastoma cells, but this is not reversed by antioxidants or ATM inhibitors.

Conclusions:

• Axitinib promotes endothelial cell senescence through an oxidative stress-dependent ATM pathway.
• Antioxidants may selectively protect endothelial cells from Axitinib, reducing systemic toxicity.
• This selective protection could maintain functional tumor vascularization for improved chemotherapy delivery.