Enhancement of radiosensitivity by the novel anticancer quinolone derivative vosaroxin in preclinical glioblastoma models
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Giovanni Luca Gravina1,2, Andrea Mancini2, Claudia Mattei3, Flora Vitale3, Francesco Marampon2, Alessandro Colapietro2, Giulia Rossi2, Luca Ventura3, Antonella Vetuschi4, Ernesto Di Cesare1, Judith A. Fox5, Claudio Festuccia2
1Department of Biotechnological and Applied Clinical Sciences, Division of Radiotherapy, University of L’Aquila, L’Aquila, Italy
2Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L’Aquila, L’Aquila, Italy
3Department of Biotechnological and Applied Clinical Sciences, Laboratory of Neurosciences, University of L’Aquila, L’Aquila, Italy
4Department of Biotechnological and Applied Clinical Sciences, Chair of Human Anatomy, University of L’Aquila, L’Aquila, Italy
5Sunesis Pharmaceuticals Inc., South San Francisco, CA, USA
Claudio Festuccia, email: [email protected]
Keywords: glioblastoma, topoisomerase II, vosaroxin, double-strand breaks, radiotherapy
Received: December 14, 2016 Accepted: March 03, 2017 Published: March 13, 2017
Purpose: Glioblastoma multiforme (GBM) is the most aggressive brain tumor. The activity of vosaroxin, a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, was investigated in GBM preclinical models as a single agent and combined with radiotherapy (RT).
Results: Vosaroxin showed antitumor activity in clonogenic survival assays, with IC50 of 10−100 nM, and demonstrated radiosensitization. Combined treatments exhibited significantly higher γH2Ax levels compared with controls. In xenograft models, vosaroxin reduced tumor growth and showed enhanced activity with RT; vosaroxin/RT combined was more effective than temozolomide/RT. Vosaroxin/RT triggered rapid and massive cell death with characteristics of necrosis. A minor proportion of treated cells underwent caspase-dependent apoptosis, in agreement with in vitro results. Vosaroxin/RT inhibited RT-induced autophagy, increasing necrosis. This was associated with increased recruitment of granulocytes, monocytes, and undifferentiated bone marrow–derived lymphoid cells. Pharmacokinetic analyses revealed adequate blood-brain penetration of vosaroxin. Vosaroxin/RT increased disease-free survival (DFS) and overall survival (OS) significantly compared with RT, vosaroxin alone, temozolomide, and temozolomide/RT in the U251-luciferase orthotopic model.
Materials and Methods: Cellular, molecular, and antiproliferative effects of vosaroxin alone or combined with RT were evaluated in 13 GBM cell lines. Tumor growth delay was determined in U87MG, U251, and T98G xenograft mouse models. (DFS) and (OS) were assessed in orthotopic intrabrain models using luciferase-transfected U251 cells by bioluminescence and magnetic resonance imaging.
Conclusions: Vosaroxin demonstrated significant activity in vitro and in vivo in GBM models, and showed additive/synergistic activity when combined with RT in O6-methylguanine methyltransferase-negative and -positive cell lines.
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