Research Papers:

Axitinib induces senescence-associated cell death and necrosis in glioma cell lines: The proteasome inhibitor, bortezomib, potentiates axitinib-induced cytotoxicity in a p21(Waf/Cip1) dependent manner

Maria Beatrice Morelli, Consuelo Amantini, Massimo Nabissi, Claudio Cardinali, Matteo Santoni, Giovanni Bernardini, Angela Santoni and Giorgio Santoni _

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Oncotarget. 2017; 8:3380-3395. https://doi.org/10.18632/oncotarget.13769

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Maria Beatrice Morelli1,2, Consuelo Amantini3, Massimo Nabissi1, Claudio Cardinali1,2, Matteo Santoni4, Giovanni Bernardini2,5, Angela Santoni2,5, Giorgio Santoni1

1School of Pharmacy, University of Camerino, Camerino, Italy

2Department of Molecular Medicine, Sapienza University, Rome, Italy

3School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy

4Department of Medical Oncology, Polytechnic University of Marche, Ancona, Italy

5I.N.M. Neuromed, Pozzilli, Isernia, Italy

Correspondence to:

Giorgio Santoni, email: [email protected]

Keywords: axitinib, glioblastoma, bortezomib, p21, senescence

Received: August 02, 2016    Accepted: November 18, 2016    Published: December 01, 2016


Glioblastoma is associated with a poor overall survival despite new treatment advances. Antiangiogenic strategies targeting VEGF based on tyrosine kinase inhibitors (TKIs) are currently undergoing extensive research for the treatment of glioma.

Herein we demonstrated that the TKI axitinib induces DNA damage response (DDR) characterized by γ-H2AX phosphorylation and Chk1 kinase activation leading to G2/M cell cycle arrest and mitotic catastrophe in U87, T98 and U251 glioma cell lines. Moreover, we found that p21(Waf1/Cip1) increased levels correlates with induction of ROS and senescence-associated cell death in U87 and T98 cell lines, which are reverted by N-acetyl cysteine pretreatment. Conversely, U251 cell line showed a resistant phenotype in response to axitinib treatment, as evidenced by cell cycle arrest but no sign of cell death.

The combinatorial use of axitinib with other therapies, with the aim of inhibiting multiple signaling pathways involved in tumor growth, can increase the efficiency of this TKI. Thus, we addressed the combined effects of axitinib with no toxic doses of the proteasome inhibitor bortezomib on the growth of U87 and T98 axitinib-sensitive and axitinib-resistant U251 cell lines. Compared to single treatments, combined exposure was more effective in inhibiting cell viability of all glioma cell lines, although with different cell death modalities. The regulation of key DDR and cell cycle proteins, including Chk1, γ-H2AX and p21(Waf1/Cip1) was also studied in glioma cell lines.

Collectively, these findings provide new perspectives for the use of axitinib in combination with Bortezomib to overcome the therapy resistance in gliomas.

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