Nitroxoline induces apoptosis and slows glioma growth in vivo

The development of more effective therapeutic agents for high-grade gliomas remains a major challenge in neuro-oncology. Even with state-of-the-art surgical techniques, radiation, and temozolomide treatment, the median survival for the most aggressive gliomas (grade IV, glioblastoma) is 12–16 months from diagnosis and has improved little over the past 10 years.1,2 The ultimate failure of available treatments is attributed to drug resistance, infiltrative properties of high-grade gliomas, and the inability to completely resect invading tumor cells. Molecular mechanisms that enable glioma cells to resist apoptosis, ultimately leading to treatment failure, are only partially elucidated. Glioma cells have unique properties that enable them to break down the extracellular matrix and invade adjacent brain parenchyma. The expression of plasminogen activators, matrix metalloproteinases, and cysteine proteases all correlate with glioma progression, grade, and more invasive phenotype. For these reasons, more effective therapeutic agents could be sought among the compounds that can efficiently induce apoptosis while inhibiting tumor cell invasion. Recently, the FDA-approved antibiotic 8-hydroxy-5-nitroquinoline (nitroxoline) has regained attention due to its more potent anticancer properties than similar compounds that are also structurally related to clioquinol and 8-hydroxyquinoline.3 Nitroxoline was found to be one of the most effective inhibitors of angiogenesis and type 2 methionine aminopeptidase (MetAP2) among 175 000 compounds from a library of FDA-approved drugs.4 The same study demonstrated nitroxoline's ability to significantly inhibit growth of breast and bladder cancer xenografts in vivo.4 Apart from its role in the inhibition of angiogenesis, nitroxoline was recently shown to inhibit expression of cysteine proteinase cathepsin B (catB).5,6 CatB is elevated in many neoplasms including melanoma and breast, lung, ovarian, colorectal, and brain cancers.7,8 High levels of catB are found at the invasive edge of anaplastic astrocytomas and glioblastoma and in their cell culture media.9 Therefore, as a compound with the potential to suppress glioma invasion, nitroxoline has several advantages including a long history of human use (having been prescribed for urinary tract infections for more than 50 years in Europe10), tolerable side effects, and a favorable pharmacokinetic profile. As an already FDA-approved drug, nitroxoline has the potential to quickly enter clinical trials as an anticancer agent if it is shown to be effective for specific tumor types. Animal models that faithfully mimic the glioma microenvironment are necessary to evaluate drug therapies. Orthotopic xenograft models that use glioma/glioblastoma-derived cell lines have been commonly used for interventional studies, but their clinical relevance is questionable because of the inability to recapitulate many of the features that characterize high-grade gliomas. Several novel tumor models that more closely mimic human gliomas have been recently introduced.11–13 In the current work, we employ a genetically engineered mouse model based on adult neural stem cell-specific phosphatase and tensin homolog (PTEN) deletion and overexpression of human Kirsten rat sarcoma viral oncogene homolog KRASG12D capable of recapitulating many of the characteristics of human glioma. This glioma model was combined with magnetic resonance imaging (MRI) to evaluate treatment efficacy and help develop MRI biomarkers that can be used to monitor and predict treatment response to nitroxoline.