Monoamine oxidase A (MAO A) inhibitors decrease glioma progression

// Swati Kushal 1, 5, * , Weijun Wang 2, 5, * , Vijaya Pooja Vaikari 1, 5 , Rajesh Kota 1, 5 , Kevin Chen 1, 5 , Tzu-Shao Yeh 1, 5, 6 , Niyati Jhaveri 3 , Susan L. Groshen 7 , Bogdan Z. Olenyuk 1 , Thomas C. Chen 2, 5 , Florence M. Hofman 2, 3, 5 , Jean C. Shih 1, 4, 5, 6 1 Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA 2 Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA 3 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA 4 Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA 5 USC-Taiwan Center for Translational Research, Los Angeles, California, USA 6 Program for Cancer Biology and Drug Discovery, College of Pharmacy, Taipei Medical University, Taipei, Taiwan 7 Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA * These authors have contributed equally to this work Correspondence to: Jean C. Shih, e-mail: jcshih@usc.edu Florence M. Hofman, e-mail: hofman@usc.edu 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 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.