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The Up-Regulation of Oxidative Stress As a Potential Mechanism of Novel MAO-B Inhibitors for Glioblastoma Treatment

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The Up-Regulation of Oxidative Stress As a Potential Mechanism of Novel MAO-B Inhibitors for Glioblastoma Treatment molecules Article The Up-Regulation of Oxidative Stress as a Potential Mechanism of Novel MAO-B Inhibitors for Glioblastoma Treatment Guya Diletta Marconi 1, Marialucia Gallorini 1 , Simone Carradori 1,* , Paolo Guglielmi 2, Amelia Cataldi 1 and Susi Zara 1 1 Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; [email protected] (G.D.M.); [email protected] (M.G.); [email protected] (A.C.); [email protected] (S.Z.) 2 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy; [email protected] * Correspondence: [email protected], Tel.: +39-0871-355-4583 Academic Editor: Simona Collina Received: 24 April 2019; Accepted: 23 May 2019; Published: 25 May 2019 Abstract: Gliomas are malignant brain tumors characterized by rapid spread and growth into neighboring tissues and graded I–IV by the World Health Organization. Glioblastoma is the fastest growing and most devastating IV glioma. The aim of this paper is to evaluate the biological effects of two potent and selective Monoamine Oxidase B (MAO-B) inhibitors, Cmp3 and Cmp5, in C6 glioma cells and in CTX/TNA2 astrocytes in terms of cell proliferation, apoptosis occurrence, inflammatory events and cell migration. These compounds decrease C6 glioma cells viability sparing normal astrocytes. Cell cycle analysis, the Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) production were detected, revealing that Cmp3 and Cmp5 induce a G1 or G2/M cell cycle arrest, as well as a MMP depolarization and an overproduction of ROS; moreover, they inhibit the expression level of inducible nitric oxide synthase 2, thus contributing to fatal drug-induced oxidative stress. Cmp5 notably reduces glioma cell migration via down-regulating Matrix Metalloproteinases 2 and 9. This study demonstrated that our novel MAO-B inhibitors increase the oxidative stress level resulting in a cell cycle arrest and markedly reduces glioma cells migration thus reinforcing the hypothesis of a critical role-played by MAO-B in mediating oncogenesis in high-grade gliomas. Keywords: Glioblastoma; MAO-B inhibitors; oxidative stress; migration 1. Introduction Gliomas are the first brain tumors assumed to originate from the neuroglial stem or from progenitor cells, characterized by inappropriate proliferation, infiltration into neighboring normal brain tissue and the disruption of the normal functioning of the brain. Based on their histological appearance, gliomas are conventionally classified as astrocytic, oligodendroglial or ependymal tumors and attributed by the World Health Organization grades I–IV, which denote disparate levels of malignancy [1]. Glioblastoma (GBM), a grade IV astrocytoma notoriously treatment–resistant brain cancer, is the greatest destructive brain tumor, largely due to the limited effects of conventional post-surgical chemotherapeutic agents and to irradiation [2]. A better understanding of the mechanism underlying the destructive nature of GBM could improve radio-, chemo- and gene therapy. More effective GBM therapeutic strategies are urgently needed. Unfortunately, the present therapies for high-grade gliomas are not an effective approach; after preliminary diagnosis, patients receive a maximal surgical resection, concomitant radiotherapy Molecules 2019, 24, 2005; doi:10.3390/molecules24102005 www.mdpi.com/journal/molecules Molecules 2019, 24, 2005 2 of 16 and chemotherapy with Temozolomide (TMZ), the currently used chemoterapeutic agent for GBM treatment.Molecules The 2019 TMZ, 24, x FOR raised PEER the REVIEW prognosis of GBM patients because it can cross the blood-brain2 of barrier17 and promote glioma cell death by alkylating DNA, even if TMZ resistance could be one of the major reasonsand why chemotherapy treatments with are Temozolomide not effective [3 (TMZ),]. the currently used chemoterapeutic agent for GBM Monoaminetreatment. The Oxidase TMZ raised (MAO) the prognosis catalyzes of GBM the oxidative patients because deamination it can cross of the a range blood-brain of monoamines, barrier and promote glioma cell death by alkylating DNA, even if TMZ resistance could be one of the major including 5-hydroxytryptamine (5-HT, serotonin), histamine and the catecholamines dopamine, reasons why treatments are not effective [3]. noradrenaline and adrenaline. The two isoenzymes of MAO (MAO-A and MAO-B) are present in Monoamine Oxidase (MAO) catalyzes the oxidative deamination of a range of monoamines, mostincluding mammalian 5-hydroxytryptamine tissues. They are (5-HT, not uniformly serotonin), distributed histamine inand the the human catecholamines brain, and dopamine, the principal form innoradrenaline the basal ganglia and adrenaline. is MAO-B. The Over two theisoenzymes past several of MAO decades, (MAO-A MAO-B and MAO-B) inhibitors are showed presentto inhave potentialmost use mammalian in the treatment tissues. They of several are not neurodegenerative uniformly distributed disorders, in the human including brain, and Parkinson’s the principal disease and Alzheimer’sform in the basal disease ganglia [4]. is MAO-B. Over the past several decades, MAO-B inhibitors showed to have However,potential use in in the the paper treatment of Gabilondo of several neurodeg et al. [5],enerative it was reporteddisorders, thatincluding a remarkable Parkinson’s and disease selective increaseand in Alzheimer’s MAO-B activity disease is [4]. also detected in human gliomas. This could be explained by an augmented number ofHowever, astrocytes in the as paper well asof aGabilondo higher content et al. [5], of it MAO-Bwas reported in tumoral that a remarkable astrocytes and with selective respect to increase in MAO-B activity is also detected in human gliomas. This could be explained by an normal ones [5], highlighting that the overexpression of MAO-B could be related with high-grade augmented number of astrocytes as well as a higher content of MAO-B in tumoral astrocytes with glioma, and thus defining MAO-B as a promising target for the development of novel therapies respect to normal ones [5], highlighting that the overexpression of MAO-B could be related with high- for cancer.grade glioma, To better and understandthus defining theMAO-B role as played a promising by MAO-B target for inhibitors the development in the treatmentof novel therapies of glioma, the aimfor iscancer. to evaluate To better two understand newly synthesized the role played compounds, by MAO-B inhibitors namely in Cmp the 3treatmentand Cmp of5 glioma,(Figure the1)[ 6], alongaim with is to two evaluate approved two newly selective synthesized MAO-B compounds, inhibitors (deprenyl namely Cmp and3 and safinamide). Cmp5 (Figure These 1) [6], compounds along werewith the best-in-class two approved derivatives, selective MAO-B within inhibitors the hydrazothiazole (deprenyl and safinamide). scaffold, endowed These compounds with a potent were and selectivethe best-in-class hMAO-B inhibition derivatives, in thewithin low the nanomolar hydrazothiazole range comparablescaffold, endowed to the with clinically a potent used and drugs. selective hMAO-B inhibition in the low nanomolar range comparable to the clinically used drugs. The Selectivity Index (SI) was expressed as IC50 hMAO-A/IC50 hMAO-B. They were shown to act as reversibleThe Selectivity and competitive Index (SI) inhibitors. was expressed We also as IC assessed50 hMAO-A/IC the in50 vitro hMAO-B.stability They of were pH andshown temperature to act as in reversible and competitive inhibitors. We also assessed the in vitro stability of pH and temperature forced conditions [7]. in forced conditions [7]. The aimThe ofaim this of this work work is tois investigateto investigate the the biological biological response response of of rat rat C6 C6 glioma glioma cell cellline lineand andCTX CTX TNA2TNA2 astrocytes astrocytes after after treatment treatment with with these these two two novelnovel MAO-B inhibitors inhibitors in interms terms of cell of cellproliferation, proliferation, apoptosisapoptosis occurrence, occurrence, inflammatory inflammatory events events and and cell cell migration.migration. Figure 1. Structures and monoamine oxidase (MAO) inhibitory activity of the tested compounds. Figure 1. Structures and monoamine oxidase (MAO) inhibitory activity of the tested compounds. 2. Results 2. Results 2.1. Effects of MAO-B Inhibitors on Rat C6 Glioma and on CTX TNA2 Astrocytes Cell Viability 2.1. Effects of MAO-B Inhibitors on Rat C6 Glioma and on CTX TNA2 Astrocytes Cell Viability Two novel, selective and potent MAO-B inhibitors, Compound 3 (Cmp3) and Compound 5 (Cmp5), wereTwo selectednovel, selective and kept and for potent further MAO-B investigations inhibitors, (FigureCompound1). The3 (Cmp e ffects3) and of CmpCompound3 and Cmp5 5 were(Cmp evaluated5), were by selected means and of MTT kept assayfor further on rat inve C6stigations glioma (Figure cell line 1). compared The effects withof Cmp non-tumoral3 and Cmp5 CTX were evaluated by means of MTT assay on rat C6 glioma cell line compared with non-tumoral CTX TNA2 astrocytes. Cmp3 and Cmp5 were tested individually and compared to TMZ, the widely used TNA2 astrocytes. Cmp3 and Cmp5 were tested individually and compared to TMZ, the widely used drugdrug in GBM in GBM treatment, treatment, to evaluateto evaluate the the eff effectect on on cell cell viability.viability. CmpCmp3 and3 and Cmp Cmp5 were5 were administered administered at at doses doses rangingranging from from 3.125
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