Monoamine oxidase A (MAO A) inhibitors decrease glioma progression
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Swati Kushal1,5,*, Weijun Wang2,5,*, Vijaya Pooja Vaikari1,5, Rajesh Kota1,5, Kevin Chen1,5, Tzu-Shao Yeh1,5,6, Niyati Jhaveri3, Susan L. Groshen7, Bogdan Z. Olenyuk1, Thomas C. Chen2,5, Florence M. Hofman2,3,5, Jean C. Shih1,4,5,6
1Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA
2Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
3Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
4Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
5USC-Taiwan Center for Translational Research, Los Angeles, California, USA
6Program for Cancer Biology and Drug Discovery, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
7Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
*These authors have contributed equally to this work
Jean C. Shih, e-mail: [email protected]
Florence M. Hofman, e-mail: [email protected]
Keywords: MAO A, MAO A inhibitors, glioma, TMZ-resistant, near-infrared dye conjugate
Received: November 20, 2015 Accepted: January 29, 2016 Published: February 09, 2016
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.
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