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Potential Anticancer Application of Polyamine Oxidation Products Formed by Amine Oxidase: a New Therapeutic Approach

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Potential Anticancer Application of Polyamine Oxidation Products Formed by Amine Oxidase: a New Therapeutic Approach Amino Acids (2010) 38:353–368 DOI 10.1007/s00726-009-0431-8 REVIEW ARTICLE Potential anticancer application of polyamine oxidation products formed by amine oxidase: a new therapeutic approach E. Agostinelli • G. Tempera • N. Viceconte • S. Saccoccio • V. Battaglia • S. Grancara • A. Toninello • R. Stevanato Received: 10 August 2009 / Accepted: 20 October 2009 / Published online: 10 December 2009 Ó Springer-Verlag 2009 Abstract The polyamines spermine, spermidine and biocompatible hydrogel polymers. Since both wild-type and putrescine are ubiquitous cell components. These molecules MDR cancer cells after pre-treatment with MDL 72527, a are substrates of a class of enzymes that includes monoamine lysosomotropic compound, are sensitized to subsequent oxidases, diamine oxidases, polyamine oxidases and copper- exposure to BSAO/spermine, it is conceivable that combined containing amine oxidases. Amine oxidases are important treatment with a lysosomotropic compound and BSAO/ because they contribute to regulate levels of mono- and spermine would be effective against tumor cells. It is of polyamines. In tumors, polyamines and amine oxidases are interest to search for such novel compounds, which might be increased as compared to normal tissues. Cytotoxicity promising for application in a therapeutic setting. induced by bovine serum amine oxidase (BSAO) and spermine is attributed to H2O2 and aldehydes produced Keywords Polyamine Á Amine oxidases Á Tumor cells Á by the reaction. This study demonstrated that multidrug- Multidrug resistance Á Hyperthermia resistant (MDR) cancer cells (colon adenocarcinoma and melanoma) are significantly more sensitive than the corre- Abbreviations sponding wild-type (WT) ones to H O and aldehydes, the 2 2 ADR Adriamycin-resistant cells products of BSAO-catalyzed oxidation of spermine. Trans- ALDH Aldehyde dehydrogenase mission electron microscopy (TEM) observations showed AO Amine oxidase major ultrastructural alterations of the mitochondria. These APAO N1-Acetylpolyamine oxidase were more pronounced in MDR than in WT cells. Increasing BSAO Bovine serum amine oxidase the incubation temperature from 37 to 42°C enhances cyto- CHO Chinese hamster ovary toxicity in cells exposed to spermine metabolites. The CuAO Copper amine oxidase combination BSAO/spermine prevents tumor growth, par- Cu/TPQ-AO Amine oxygen oxidoreductase copper- ticularly well if the enzyme has been conjugated to a containing DAO Diamine oxidase E. Agostinelli (&) Á G. Tempera Á N. Viceconte Á S. Saccoccio DFMO Difluoromethylornithine Department of Biochemical Sciences – SAPIENZA University DX Doxorubicin-resistant cells of Rome and CNR, Biology and Molecular Pathology Institutes, FAD Flavin adenine dinucleotide Piazzale Aldo Moro 5, 00185 Rome, Italy e-mail: [email protected] hVAP-1 Human vascular adhesion protein-1 LoVo Colon adenocarcinoma cell V. Battaglia Á S. Grancara Á A. Toninello LOX Lysyl oxidase Department of Biological Chemistry, University of Padua, M14 Melanoma cell 35121 Padua, Italy MAO Monoamine oxidase 1 4 R. Stevanato MDL 72527 N ,N -bis(2,3-butadienyl)-1,4- Department of Physical Chemistry, butanediamine University of Venice ‘‘Ca’ Foscari’’, MDR Multidrug-resistant Dorsoduro 2137, 30123 Venice, Italy 123 354 E. Agostinelli et al. NSAIDS Non-steroidal anti-inflammatory drugs they catalyze the formation of metabolites (ammonia and PAO Polyamine oxidase amino acids) that can be excreted via the kidneys (Seiler PEG Polyethylene glycol 1992). Products of polyamine oxidation are toxic to cells. P-gp P-glycoprotein In serum-containing cell cultures, cytotoxicity of poly- ROS Reactive oxygen species amines correlates with their property as substrates of serum SAO Serum amine oxidase amine oxidases (Morgan 1988). Oxidation represents a SH Thiol groups crucial reaction in polyamine metabolism, by means of SMO Spermine oxidase which these polycations enter the catabolic routes for SSAO Semicarbazide-sensitive amine oxidase irreversible inactivation and elimination. Mono-, di- and TEM Transmission electron microscopy polyamines, as well as several N-acyl amines, are oxida- LTQ Lysine tyrosylquinone tively deaminated by amine oxidases (AOs) in a reaction TNFa Tumor-necrosis factor a consuming O2 and H2O, either by the removal of one TPQ 2,4,5-Trihydroxyphenylalaninequinone primary amino group or by the cleavage of the molecule at VAP-1 Vascular adhesion protein-1 the secondary nitrogen atoms and oxidation of the terminal WR 1065 Aminothiol N-(2-mercaptoethyl)- carbon of the remaining molecule to an aldehyde group 1,3-propanediamine during the same catalytic cycle. Oxidative deamination WT Wild-type produces aldehyde, amine and H2O2 in stoichiometric amounts according to the following equations (Bellelli et al. 2000; Agostinelli et al. 2009a; Edmondson et al. 2007, 2009): 1. R–CH –NH ? H O ? O ? R–CHO ? NH ? Introduction 2 2 2 2 3 H2O2 2. R–CH –NH–CH –R ? H O ? O ? R–CHO ? The polyamines spermine, spermidine and putrescine are 2 2 2 2 NH –CH -R ? H O ubiquitous cell components, which are essential for cell 2 2 2 2 1. Cleavage at the primary amino group (operated by proliferation and differentiation (Pegg 1988). They attract both copper and FAD-dependent AOs). interest because of their multiple functions in cell biology 2. Cleavage at the secondary amino group (operated by (Cohen 1998) including, among many others, cell cycle the FAD-dependent AOs). regulation, gene expression and signal transduction (Bachrach et al. 2001; Childs et al. 2003). Moreover, it has This minireview deals with the fundamental struc- been demonstrated that intracellular accumulation of tural properties of a Cu/TPQ (copper/2,4,5-trihydrox- polyamines can induce programmed cell death (or apop- yphenylalaninequinone) AO isolated from bovine serum tosis) in various cell types (Tobias and Kahana 1995) (BSAO) (Turini et al. 1982), involving the formation of a through activation of the caspase cascade (Stefanelli et al. Schiff base between the amine substrate and the organic 1998, 1999). The activation of caspases is triggered by the cofactor (Bellelli et al. 2000; Agostinelli et al. 2009a). release of mitochondrial cytochrome c (Ghafourifar et al. Moreover, it describes the possibility of using purified 1999; Andreyev and Fiskum 1999; Hengartner 2000), BSAO, in the presence of exogenous spermine or endog- which has been shown to be induced by spermine or enous polyamines, to induce cytotoxicity, on several spermidine (Stefanelli et al. 2000). The natural polyamines human tumor cell lines in vitro (Calcabrini et al. 2002; are substrates of several flavin adenine dinucleotide (FAD)- Agostinelli et al. 2009b) or after injection of the enzyme dependent enzymes [monoamine oxidase (MAO), poly- into the tumor in vivo (Averill-Bates et al. 2005). Amine amine oxidase (PAO), spermine oxidase (SMO)] and of oxidases metabolize preferentially polyamines (spermine copper amine oxidases (CuAOs) [diamine oxidase (DAO), and spermidine) to generate the reaction products H2O2 and serum amine oxidases (SAO), lysyl oxidase (LOX)] (A- aldehyde(s) (Fig. 1) (Agostinelli and Seiler 2006). Such rancia et al. 2004; Agostinelli et al. 2004). Two isoforms, toxic products are able to induce stress-activated signal termed monoamine oxidases A and B, are present in transduction pathways, leading to cell death, by necrosis or approximately the same amounts in the outer mitochondrial apoptosis (Lindsay and Wallace 1999; Seiler and Raul membrane (Edmondson et al. 2009; La Regina et al. 2007) 2005; Agostinelli et al. 2006a). and inhibition of either of them has been demonstrated to The research for innovative therapeutic approaches, protect cells against apoptosis (Malorni et al. 1998; Pat- based on the use of new pharmacological agents or drug erson and Tatton 1998). PAO is involved in the homeo- associations effective against resistant tumors and, possi- static regulation of polyamine pools. The other oxidases are bly, with a low degree of undesirable side effects, is important for the terminal catabolism of polyamines, i.e., gaining interest in clinical oncology. In our study carried 123 Anticancer activity of polyamine enzymatic oxidation products 355 inhibitor sensitivity, and subcellular localizations (Agosti- nelli et al. 2004). In the most common classification, these enzymes (amine: oxygen oxidoreductases, AOs, E.C. 1.4.3.4.) are divided into two classes, based on the chem- ical nature of the cofactors involved (Mondovı` et al. 1989). The first class is characterized by the presence of FAD- AOs, ubiquitous enzymes in the cells of most mammalian species, and the PAOs found principally in vertebrates and plants (Binda et al. 2002). The second class consists of enzymes having a tightly bound Cu2? ion and a carbonyl- type group identified as either a 6-hydroxydopa quinone (2,4,5-trihydroxyphenylalaninequinone, TPQ) or a lysine tyrosylquinone (LTQ) at their active site. TPQ is easily detected, thanks to its pink absorption and its reactivity toward semicarbazide and phenylhydrazine; however, its chemical identification is relatively recent (Janes et al. 1990). Both FAD- and Cu2?/TPQ-amine oxidases have been isolated and characterized from numerous organisms ranging from microorganisms, plants and mammals. FAD- AOs are mainly intracellular enzymes, often associated with the outer mitochondrial membrane (Edmondson et al. 2007, 2009), whereas CuAOs are either intra- or extracel- lular enzymatic proteins, or in some cases integral plasma membrane proteins (Agostinelli et al. 2007a, 2009a; Floris
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