Nitroxoline induces apoptosis and slows glioma growth in vivo
Jelena Lazovic1, Lea Guo1, Jonathan Nakashima1
1Department of Radiological Sciences, Ronald Reagan UCLA Medical Center, Los Angeles, California (J.L., L.G., H.J.K., B.E., W.B.P.); Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California (J.N., H.W.); Department of Pathology, University of California San Diego Medical Center, San Diego, California (L.M.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California (W.Y.); Department of Biostatistics, Fielding School of Public Health and Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California (H.J.K.).
Background:
Nitroxoline is an FDA-approved antibiotic with potential antitumor activity. Here we evaluated whether nitroxoline has antiproliferative properties on glioma cell growth in vitro and in vivo using glioma cell lines and a genetically engineered PTEN/KRAS mouse glioma model.
Methods:
The effect of nitroxoline treatment on U87 and/or U251 glioma cell proliferation, cell-cycle arrest, invasion, and ability to induce an apoptotic cascade was determined in vitro. Magnetic resonance imaging was used to measure glioma volumes in genetically engineered PTEN/KRAS mice prior to and after nitroxoline therapy. Induction of apoptosis by nitroxoline was evaluated at the end of treatment using terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling (TUNEL).
Results:
Nitroxoline inhibited the proliferation and invasion of glioblastoma cells in a time- and dose-dependent manner in vitro. Growth inhibition was associated with cell-cycle arrest in G1/G0 phase and induction of apoptosis via caspase 3 and cleaved poly(ADP-ribose) polymerase. In vivo, nitroxoline-treated mice had no increase in tumor volume after 14 days of treatment, whereas tumor volumes doubled in control mice. Histological examination revealed 15%-20% TUNEL-positive cells in nitroxoline-treated mice, compared with ∼5% in the control group.
Conclusion:
Nitroxoline induces apoptosis and inhibits glioma growth in vivo and in vitro. As an already FDA-approved treatment for urinary tract infections with a known safety profile, nitroxoline could move quickly into clinical trials pending confirmatory studies.
Insights
Nitroxoline, an antibiotic, effectively inhibits glioma cell proliferation and invasion both in vitro and in vivo. This FDA-approved drug induces apoptosis and cell-cycle arrest, showing promise for future clinical trials in glioma treatment.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Nitroxoline is an FDA-approved antibiotic with demonstrated potential antitumor properties.
- Glioma is a primary brain tumor with limited treatment options.
Purpose of the Study:
- To evaluate the antiproliferative effects of nitroxoline on glioma cells in vitro.
- To assess the efficacy of nitroxoline in inhibiting glioma growth in a preclinical mouse model.
Main Methods:
- In vitro studies assessed nitroxoline's impact on glioma cell proliferation, cell-cycle arrest, invasion, and apoptosis.
- In vivo studies utilized a genetically engineered PTEN/KRAS mouse glioma model, with tumor volumes monitored by MRI and apoptosis confirmed via TUNEL staining.
Main Results:
- Nitroxoline significantly inhibited glioblastoma cell proliferation and invasion in a dose- and time-dependent manner.
- In vitro, nitroxoline induced cell-cycle arrest at the G1/G0 phase and apoptosis.
- In vivo, nitroxoline treatment prevented tumor volume increase in mice, with a higher percentage of apoptotic cells observed compared to controls.
Conclusions:
- Nitroxoline demonstrates significant efficacy in inhibiting glioma growth and inducing apoptosis both in vitro and in vivo.
- Given its FDA approval and established safety profile, nitroxoline warrants further investigation in clinical trials for glioma treatment.
