title: 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.
abstract: 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.
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.|Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Maria Beatrice
authors.initials: MB
authors.lastname: Morelli
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Amantini
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Nabissi
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.|Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cardinali
authors.affiliation: Department of Medical Oncology, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Santoni
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.|I.N.M. Neuromed, Pozzilli, Isernia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bernardini
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.|I.N.M. Neuromed, Pozzilli, Isernia, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.affiliation: School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Santoni
mesh_terms: D000077784:Axitinib; D000069286:Bortezomib / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression; D005910:Glioma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D009336:Necrosis / Q000235:genetics; D061988:Proteasome Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D007191:Indazoles; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D000069286:Bortezomib; D000077784:Axitinib
keywords: axitinib; bortezomib; glioblastoma; p21; senescence