Abstract
Glioblastoma (GBM) is an aggressive brain tumor which is currently treated with temozolomide (TMZ). Tumors usually become resistant to TMZ and recur; no effective therapy is then available. Monoamine Oxidase A (MAO A) oxidizes monoamine neurotransmitters resulting in reactive oxygen species which cause cancer. This study shows that MAO A expression is increased in human glioma tissues and cell lines. MAO A inhibitors, clorgyline or the near-infrared-dye MHI-148 conjugated to clorgyline (NMI), were cytotoxic for glioma and decreased invasion in vitro. Using the intracranial TMZ-resistant glioma model, clorgyline or NMI alone or in combination with low-dose TMZ reduced tumor growth and increased animal survival. NMI was localized specifically to the tumor. Immunocytochemistry studies showed that the MAO A inhibitor reduced proliferation, microvessel density and invasion, and increased macrophage infiltration. In conclusion, we have identified MAO A inhibitors as potential novel stand-alone drugs or as combination therapy with low dose TMZ for drug-resistant gliomas. NMI can also be used as a non-invasive imaging tool. Thus has a dual function for both therapy and diagnosis.
Highlights
Glioblastoma (GBM) is the most aggressive form of primary brain tumors, with a median survival time of 14 months from the time of diagnosis [1]
Fresh frozen human glioma tissues were analyzed for Monoamine Oxidase A (MAO A) expression; as a control, non-malignant brain tissues were examined in parallel
The data presented here demonstrate that the MAO A inhibitors, clorgyline and its conjugate near-infrared-dye MHI-148 conjugated to clorgyline (NMI), are effective in reducing TMZ-resistant tumor growth and increasing survival in glioma
Summary
Glioblastoma (GBM) is the most aggressive form of primary brain tumors, with a median survival time of 14 months from the time of diagnosis [1]. Temozolomide (TMZ) is the current therapeutic agent for treating newly diagnosed GBM either in combination with surgery and radiation or as stand-alone chemotherapy [2]. Increasing TMZ doses is not an option because this DNA alkylating agent is highly toxic to the bone marrow [3]. At this point, therapy choices are very limited. Identifying drugs that can cross the blood-brain- barrier (BBB), and are effective in decreasing the tumor progression of TMZresistant gliomas is critical
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