Abstract
PurposeGlioblastoma 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).ResultsVosaroxin 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 MethodsCellular, 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.ConclusionsVosaroxin 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.
Highlights
Glioblastoma multiforme (GBM) is an aggressive brain tumor associated with invasive behavior, high rate of recurrence, and an average survival of less than 15 months, irrespective of treatment [1,2,3]
Vosaroxin reduced tumor growth and showed enhanced activity with RT; vosaroxin/RT combined was more effective than temozolomide/RT
Vosaroxin demonstrated significant activity in vitro and in vivo in GBM models, and showed additive/synergistic activity when combined with RT in O6methylguanine methyltransferase-negative and -positive cell lines
Summary
Glioblastoma multiforme (GBM) is an aggressive brain tumor associated with invasive behavior, high rate of recurrence, and an average survival of less than 15 months, irrespective of treatment [1,2,3]. GBM tumors consist of a heterogeneous population of tumor cells and contain immune cells that, with tumor vasculature and the extracellular matrix, constitute the tumor microenvironment. Interactions among these different cell types and cytokines may promote tumor development and progression. TAMs from human neoplasms express arginase 1, interleukin (IL)-10, and transforming growth factor beta (TGF-β); these cytokines reduce the antitumor activity of T cells and natural killer cells, and modulate tumor proliferation, infiltration, and angiogenesis [10]. Cells expressing monocyte and M2 markers are found dispersed throughout the tumor parenchyma
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