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

Maria Patrizia Mongiardi, Giulia Radice, Maurizia Piras, Venturina Stagni, Simone Pacioni, Agnese Re, Sabrina Putti, Fabrizio Ferrè, Antonella Farsetti, Roberto Pallini, Daniela Barilà, Andrea Levi, Maria Laura Falchetti

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalOncogene
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Ataxia Telangiectasia
Cell Aging
Endothelial Cells
Vascular Endothelial Growth Factor Receptor
Antioxidants
Doxorubicin
Neoplasms
Oxidative Stress
Pharmaceutical Preparations
Glioblastoma
Renal Cell Carcinoma
Vascular Endothelial Growth Factor A
axitinib
Phosphotransferases
Phenotype
DNA
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

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

In: Oncogene, 01.01.2019.

Research output: Contribution to journalArticle

Mongiardi, MP, Radice, G, Piras, M, Stagni, V, Pacioni, S, Re, A, Putti, S, Ferrè, F, Farsetti, A, Pallini, R, Barilà, D, Levi, A & Falchetti, ML 2019, 'Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation', Oncogene. https://doi.org/10.1038/s41388-019-0798-2
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. / Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation. In: Oncogene. 2019.
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