Nitroxoline induces apoptosis and slows glioma growth in vivo.

Abstract

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.

• Authors: Jelena Lazovic, Lea Guo, Jonathan Nakashima, Leili Mirsadraei, William Yong, Hyun J Kim, Benjamin Ellingson, Hong Wu, Whitney B Pope
• Journal: Neuro-oncology (Neuro Oncol) Vol. 17 Issue 1 Pg. 53-62 (Jan 2015) ISSN: 1523-5866 [Electronic] England
• PMID: 25074541 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Anti-Infective Agents, Urinary
• Antineoplastic Agents
• Nitroquinolines
• nitroxoline

Topics

• Animals
• Anti-Infective Agents, Urinary (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Brain Neoplasms (drug therapy, metabolism, physiopathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Glioblastoma (drug therapy, metabolism, physiopathology)
• Mice
• Nitroquinolines (pharmacology, therapeutic use)