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.

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Acknowledgements

The study was supported by research grants from: MIUR-CNR Flagship Invecchiamento #DSB.AD009.001.004 to AL and MLF; Associazione Italiana per la Ricerca sul Cancro-AIRC IG2016-n.19069, MIUR-JPI HDHL NUTRICOG MiTyrAge, PRIN_2015LZE9944_005 and RF-2016-02362022 to DB; by RF-2016-02363460 to VS. VS has also been supported by AIRC IG2016-n.19069. We thank Dr Silvia Soddu and Prof Carlo Gaetano for their suggestions on p53 protein detection and ROS measurement, respectively.

Author information

Author notes

  1. These authors contributed equally: Maria Patrizia Mongiardi, Giulia Radice, Maurizia Piras

Affiliations

  1. CNR-Institute of Cell Biology and Neurobiology, Monterotondo Scalo, Rome, Italy

    • Maria Patrizia Mongiardi
    • , Giulia Radice
    • , Maurizia Piras
    • , Simone Pacioni
    • , Agnese Re
    • , Sabrina Putti
    • , Antonella Farsetti
    • , Andrea Levi
    •  & Maria Laura Falchetti
  2. Department of Biology, University of Rome “Tor Vergata”, Rome, Italy

    • Venturina Stagni
    •  & Daniela Barilà
  3. Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy

    • Venturina Stagni
    •  & Daniela Barilà
  4. Institute of Neurosurgery, Fondazione Policlinico Universitario “A. Gemelli”, Rome, Italy

    • Simone Pacioni
    •  & Roberto Pallini
  5. Department of Pharmacy and Biotechnology, University of Bologna Alma Mater, 40126, Bologna, Italy

    • Fabrizio Ferrè

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Contributions

MPM, GR, MP, VS, SP and AR conducted the experiments; FF performed bioinformatics analyses; RP, DB and AL analyzed and discussed the data; AF gave conceptual advice, contributed to experimental design, critical data analysis and manuscript revision; AL and MLF conceived the study and drafted the manuscript. All authors read and approved the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Antonella Farsetti or Maria Laura Falchetti.

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DOI

https://doi.org/10.1038/s41388-019-0798-2