Enhancement of radiosensitivity by the novel anticancer quinolone derivative vosaroxin in preclinical glioblastoma models

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.

The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma

“…If we considered a xenograft as equivalent to an ovoid having three diameters: the formula used was ‘TW (mg) = tumor volume (mm 3 ) = 4/3πR1 × R2 × R3 in which R1/R2/R3 are the 1/2 diameters (rays), shorter diameter is the thickness/height of tumor, larger diameters are the length and width of tumor [ 33 – 35 ]. At about 10 days after the tumor injection, 30 mice with tumor volumes of 0.5~ 0.8 cm 3 were retained and randomly divided into six groups (five mice per group with two tumors each) named (1) control (vehicle), (2) TINO (60 mg/kg at days 1, 8, and 15 q28 days, iv), (3) radiotherapy (RT, 4 Gy delivered in a single fraction [ 34 ]), and (4) TINO plus RT. These treatments were compared with standard therapies consisting of TMZ and TMZ plus RT.…”

“…The following parameters were used to quantify the antitumor effects upon different treatments as previously described [ 33 , 34 ]: (1) tumor volume measured during and at the end of experiments, (2) tumor weight measured at the end of experiment, (3) tumor progression (TP or doubling time) defined as an increase of greater than 100% of tumor volume with respect to baseline, and (4) time to progression (TTP) defined as the time for tumor progression.…”

“…Female CD1 nu/nu mice were inoculated intra-cerebrally as previously described [ 33 , 34 ] with luciferase-transfected U251 and patient-derived GBM stem cell line (GSCs-5). Just before treatment initiation (5 days after injection), animals were randomized to treatment groups of 10 mice each.…”

Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

“…These findings suggest that tumor-secreted SDF-1 stimulates glioma invasiveness and recruitment of GAMs towards hypoxic areas [65] . In addition, it has been recently shown that the antitumor activity of vosaroxin, a first in class cytotoxic agent that intercalates DNA and inhibits topoisomerase II, are also linked to increased recruitment of myeloid cells at the tumor site together with an augmented pro-inflammatory activation [66] . Likewise, the antitumor effects of chlorogenic acid (5-caffeoylquinic acid) (CHA) found in pre-clinical models of glioblastoma were associated with increased antitumor immune activations of GAMs.…”

The Small Molecule Ephrin Receptor Inhibitor, GLPG1790, Reduces Renewal Capabilities of Cancer Stem Cells, Showing Anti-Tumour Efficacy on Preclinical Glioblastoma Models

“…Nude mice were inoculated intra-cerebrally as previous described [36,37]. We injected 3 µL of cell suspension containing 3 × 10 3 U87MG or CSCs-5 luciferase tagged cells directly into the brain; the injection rate was set to 1 µL/min.…”