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

• Published in: Oncogene Vol. 38; no. 27; pp. 5413 - 5424
• Main Authors: Mongiardi, Maria Patrizia, Radice, Giulia, Piras, Maurizia, Stagni, Venturina, Pacioni, Simone, Re, Agnese, Putti, Sabrina, Ferrè, Fabrizio, Farsetti, Antonella, Pallini, Roberto, Barilà, Daniela, Levi, Andrea, Falchetti, Maria Laura
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2019; Nature Publishing Group
• Subjects: 13; 13/106; 13/31; 14; 14/19; 14/32; 38; 38/32; 38/39; 38/90; 631/337/2019; 631/80/509; Angiogenesis Inhibitors - pharmacology; Antiangiogenic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antioxidants; Antioxidants - pharmacology; Apoptosis; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins - metabolism; Axitinib; Axitinib - pharmacology; Carcinoma, Renal cell; Cell Biology; Cellular Senescence - drug effects; DNA damage; Doxorubicin; Drug delivery; Drug therapy; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium; Enzyme Activation; Genetic aspects; Glioblastoma; Glioblastoma cells; Human Genetics; Human Umbilical Vein Endothelial Cells; Humans; Inhibitor drugs; Internal Medicine; Kidney cancer; Medicine; Medicine & Public Health; Neovascularization, Pathologic - prevention & control; Oncology; Oxidative stress; Phenotypes; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Reactive Oxygen Species - metabolism; Renal cell carcinoma; Senescence; Targeted cancer therapy; Toxicity; Vascular endothelial growth factor; Vascularization
• DOI: 10.1038/s41388-019-0798-2
• ISSN: 0950-9232; 1476-5594

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.