Toxicity of Polyamines and Their Metabolic Products - ACS Publications

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Toxicity of Polyamines and Their Metabolic Products Anthony E. Pegg* Department of Cellular and Molecular Physiology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, United States ABSTRACT: Polyamines are ubiquitous and essential components of mammalian cells. They have multiple functions including critical roles in nucleic acid and protein synthesis, gene expression, protein function, protection from oxidative damage, the regulation of ion channels, and maintenance of the structure of cellular macromolecules. It is essential to maintain a correct level of polyamines, and this amount is tightly regulated at the levels of transport, synthesis, and degradation. Catabolic pathways generate reactive aldehydes including acrolein and hydrogen peroxide via a number of oxidases. These metabolites, particularly those from spermine, can cause significant toxicity with damage to proteins, DNA, and other cellular components. Their production can be increased as a result of infection or cell damage that releases free polyamines and activates the oxidative catabolic pathways. Since polyamines also have an important physiological role in protection from oxidative damage, the reduction in polyamine content may exacerbate the toxic potential of these agents. Increases in polyamine catabolism have been implicated in the development of diseases including stroke, other neurological diseases, renal failure, liver disease, and cancer. These results provide new opportunities for the early diagnosis, prevention, and treatment of disease.

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CONTENTS

1. 2. 3. 4. 5. 6.

Introduction Polyamine Structure and Function Polyamine Biosynthesis Toxicity of Polyamines Polyamine Metabolism and Homeostasis Oxidases Attacking Polyamine 6.1. Diamine Oxidase 6.2. Serum Amine Oxidase and Related Enzymes 6.3. Acetylpolyamine Oxidase (APAO) 6.4. Spermine Oxidase (SMO) 7. Overall Role of Oxidases in Controlling Polyamine Content 8. Toxicity of Polyamine Oxidation Products 8.1. Polyamine Derived Aldehydes Including Acrolein 8.2. Reactive Oxygen Species 9. Protective Effects of Polyamines against Oxidative Stress and Inflammation 9.1. Glutathionylspermidine and Trypanothione 10. Pathophysiology Associated with Polyamine Oxidation 10.1. Stroke and Neurological Diseases 10.2. Renal Failure 10.3. Liver Damage 10.4. Inflammation and Cancer Initiation 10.4.1. Prostate Cancer 10.4.2. Gastrointestinal Cancers 10.4.3. Skin Cancer © 2013 American Chemical Society

11. Potential Therapeutic Implications of Polyamine Oxidation 11.1. Polyamine Analogues 11.2. Possible Use of Polyamine Oxidase and a Polyamine Substrate for Therapy 12. Conclusions Author Information Corresponding Author Notes Abbreviations References

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1. INTRODUCTION Polyamines are small positively charged molecules that are found in virtually all living cells.1 They are essential for life in eukaryotes and play critical roles in multiple cellular functions. Maintenance of the appropriate polyamine level is necessary to allow these functions, and excess polyamine levels can lead to toxicity. Toxic effects also result as a result of polyamine catabolism, which can generate reactive aldehydes and reactive oxygen species. The resulting oxidative stress may be exacerbated by a fall in polyamines since polyamines and, in some species their metabolites, have important roles as antioxidants. Rapidly increasing reports in the literature have now identified polyamine catabolism as a contributory factor to

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Received: September 1, 2013 Published: November 13, 2013 1782

dx.doi.org/10.1021/tx400316s | Chem. Res. Toxicol. 2013, 26, 1782−1800

Chemical Research in Toxicology

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Figure 1. Some physiological diamines, polyamines, and related compounds. Mammals synthesize putrescine, spermidine, and spermine. Mammalian tissues may also contain small amounts of agmatine from dietary sources. Plants synthesize agmatine, putrescine, spermidine, spermine, and thermospermine and, in some species, other polyamine such as sym-homospermidine. Microorganisms contain a wide variety of polyamines depending on the species. E. coli synthesizes agmatine, putrescine, spermidine, and N1-glutathionylspermidine. S. cerevisiae yeast synthesizes putrescine, spermidine, and spermine. Thermophiles contain high levels of a wide variety of polyamines, including thermine, caldine, and thermospermine and many others (not shown), which are essential for growth at high temperatures. A wide variety of other natural polyamines occur in living cells. Hypusine, Nε-(4-amino-2-hydroxybutyl)-lysine, is formed from spermidine as a post-translational modification in the protein eIF5A from spermidine in all eukaryotes, and this modification is essential for viability. Trypanothione, N1,N8-bis(glutathionyl)spermidine, is formed in trypanosomes and is essential for protection from oxidative damage.

the development of a variety of clinical conditions. This work, which is the focus of this review, provides new insights into the diagnosis, prevention, and retardation of the progress of important human diseases.

Gene deletions causing an inability to produce putrescine or spermidine are lethal in mice at very early embryonic stages.14,15 The absence of spermine in Gy mice, which have an X-linked chromosomal deletion of the spermine synthase gene, causes a severe phenotype including short life span, sterility, deafness, neurological abnormalities, and small size.16,17 Humans with mutations in the spermine synthase gene reducing the ability to produce spermine have SnyderRobinson syndrome characterized by intellectual disability, hypotonia, facial dysmorphism, speech defects, asthenic body build and diminished body bulk, and osteoporosis.18−20 However, spermine is not required for the growth of Saccharomyces cerevisiae,21 and many microorganisms do not contain this tetramine. Plants contain the three polyamines found in mammals and require putrescine and spermidine. Spermine synthase is not essential for normal plant growth, but plants also synthesize an isomer thermospermine (Figure 1).22 Thermospermine synthase is an essential gene whose inactivation causes dwarfism and abnormal xylem differentiation.23,24 Spermidine is essential in all eukaryotes including yeast as a precursor of hypusine [Nε-(4-amino-2-hydroxybutyl)-lysine] (Figure1), a post-translational modification of the transcription initiation factor eIF5A that is required for translation elongation particularly at consecutive proline residues.10,25,26 Mutant Escherichia coli lacking the biosynthetic enzymes needed to

2. POLYAMINE STRUCTURE AND FUNCTION There are many natural diamines and polyamines (Figure 1). In mammals, the three naturally occurring members of this family are spermine, spermidine, and putrescine (Figure 1), and all are needed for normal growth and development. Many of the longer polyamines are present in thermophiles2,3 (hence the names such as thermine, caldine, and thermospermine), although they are also found in other organisms. Very long polyamines are used for biomineralization of the shell in diatoms.4,5 Polyamines are strongly positively charged at physiological pH and bind to acidic sites on cellular components including nucleic acids, proteins, and membranes. They have a multitude of functions. These include protective effects on membrane structure/function and nucleic acid structure and stability; antioxidant effects; roles in protein and nucleic acid synthesis; the regulation of the expression for many genes by both transcriptional and translational effects; the control of the activity of ion channels; and the modulation of kinase activities.6−13 1783



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Figure 2. Synthesis of polyamines. (A) Condensation pathways for the formation of polyamines. Reaction of L-aspartic-β-semialdehyde with putrescine forms carboxyspermidine, which is then decarboxylated forming spermidine. Similar reactions using the same enzymes with 1,3diaminopropane rather than putrescine form sym-norspermidine. Polyamines with multiple aminobutyl groups are formed by an enzyme using NAD and spermidine to produce 1,3-diaminopropane and a 4-aminobutyraldehyde intermediate. This generates the product by condensation with putrescine to form sym-homospermidine and 1,3-diaminopropane. Some species use a similar enzyme that replaces spermidine with a second molecule of putrescine to form sym-homospermidine and ammonia. (B) Aminopropyltransferase pathway for polyamine synthesis. SAdenosylmethionine is decarboxylated to form the aminopropyl-donor decarboxylated S-adenosylmethionine (dcAdoMet). Aminopropyltransferase enzymes then use dcAdoMet and an amine acceptor to form the higher polyamines. Some aminopropyltransferases such as spermidine and spermine synthases from mammalian, yeast and plant sources are highly specific using only putrescine or spermidine as acceptors and, in the case of spermine synthase, adding the aminopropyl group only to the N1-position. Similarly, the plant thermospermine synthase places the aminopropyl group only on the N8-position of spermidine. Other aminopropyl transferases such as those in some thermophiles including Thermotoga maritima and Thermus thermophilus are much less specific and can use a variety of amine acceptors including 1,3-diaminopropane, thermine, caldine, and agmatine.

occurs in some plants and microorganisms in which L-arginine is decarboxylated forming agmatine (Figure 1).28,29 This can then be converted to putrescine either by the reaction of agmatinase or by the combined actions of agmatine deiminase and N-carbamoylputrescine amidohydrolase.30−32 Mammals contain only the ornithine decarboxylase (ODC) pathway, and ODC is a critical enzyme in the maintenance of polyamine content. Two pathways are known for the production of polyamines. Many microorganisms use a condensation pathway in which Laspartic-β-semialdehyde is used to provide the aminopropyl

produce putrescine can grow, albeit very slowly, in the absence of polyamines, but the addition of putrescine (which also restores spermidine) enhances the expression of more than 300 genes, which form a “polyamine modulon” and allows normal growth.7,27

3. POLYAMINE BIOSYNTHESIS Diamines such as putrescine, cadaverine, and 1,3-diaminopropane (Figure 1) are formed by the decarboxylation of the relevant amino acid (L-ornithine, L-lysine, and L-1,4-diaminobutyric acid, respectively). An alternative pathway to putrescine 1784



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Figure 3. Reactions catalyzed by spermidine/spermine-N1-acetyltransferase (SSAT). SSAT is specific for the acetylation of terminal aminopropyl groups. Thus, spermidine is attacked only at one end, whereas spermine can be acetylated at either end, and N1-acetylspermine can undergo a second reaction with SSAT to form N1,N12-diacetylspermine.

groups (Figure 2A).33 For example, reaction of L-aspartic-βsemialdehyde with putrescine forms carboxyspermidine, which is then decarboxylated to form spermidine. A similar type of reaction can be used to form polyamines with multiple aminobutyl groups by an enzyme using NAD and putrescine to form a 4-aminobutyralehyde intermediate, which generates the product by condensation with a second molecule of putrescine or spermidine (Figure 2A).34,35 The pathway for the production of polyamines in mammals, plants, fungi, and many bacteria including E. coli involves decarboxylated S-adenosylmethionine (dcAdoMet) as the aminopropyl donor (Figure 2B).36−38 Aminopropyltransferases use dcAdoMet and an amine acceptor to form the higher polyamines. Some aminopropyltransferases such as those from thermophiles are relatively nonspecific and can form polyamines of differing lengths.3,39,40 In contrast, the mammalian and plant aminopropyltransferases are highly specific. Spermidine synthase uses putrescine as a substrate to form spermidine, whereas spermine synthase adds the aminopropyl group to the N8 of spermidine forming spermine.40,41 Plants contain a third aminopropyltransferase, thermospermine synthase, that attacks the N1 end of spermidine producing thermospermine.40,42

cations such as magnesium from these sites.45 Inhibition of blood clotting and transitory falls in blood pressure and respiratory symptoms were seen shortly after administration to experimental animals, and neurotoxicity leading to renal insufficiency developed after a few days. Spermine was much more (ca. 20 times) nephrotoxic than spermidine. Injected polyamines may cause toxicity via effects at intracellular, extracellular, or membrane sites. It is also possible that oxidation products, which, as described extensively in section 8 below, are highly toxic, are generated by extracellular oxidases and mediate these effects. In these early experiments, intravenous injections of beef plasma amine oxidase actually protected the kidney from the toxic effects of spermine. However, as pointed out by the authors, this could be due to the degradation of spermine before it reached the renal epithelium and was converted into short-lived toxic metabolites active locally. 43 In many cases where polyamines have been added to cell cultures, the resulting toxicity is due to the presence in the culture medium of bovine serum amine oxidase. This acts on the polyamine to generate highly toxic intermediates (see section 6. 2). All studies where this artifact is not eliminated or controlled for by the use of amine oxidase inhibitors or the use of serum free medium cannot be interpreted unequivocally to show a direct toxic effect of polyamines. Unfortunately, this applies to many publications since the adverse effects of polyamine addition to cell growth and viability have been rediscovered on multiple occasions. The well-known ability of spermine or spermidine to kill spermatozoa also requires the presence of high levels of amine oxidases.43,46 Seminal plasma in many species including humans contains high levels of spermine originating from the prostatic secretions,46,47 and an oxidase active on spermine has been purified from seminal plasma.48 Sperm contain a surface aldo-

4. TOXICITY OF POLYAMINES Despite the absolute need for polyamines, it has been known for more than 50 years that spermine and spermidine have acute toxic effects when injected into animals,43 and many early studies have observed toxic effects of polyamines on the growth and viability of microorganisms, spermatozoa, cultured mammalian cells, and viruses.43,44 This toxicity could be due to direct action of the polyamines themselves. It is likely that excess intracellular polyamines derange cellular metabolism including protein synthesis by binding to acidic sites in nucleic acids, membranes, and proteins and/or by displacing other 1785



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keto reductase that protects against acrolein and other reactive aldehyde species,49 and this activity may protect against the limited amount of oxidation products produced under physiological conditions.

Severe pathophysiological effects have been observed in rodents that have continuous hugely elevated levels of SSAT due to the transgenic expression of SSAT.51,62,66,67 These include hair loss, female infertility, weight loss, CNS effects, altered carbohydrate and lipid metabolism, a tendency to develop pancreatitis and altered responses to chemical carcinogens. They result from not only alterations in polyamine content but also to the effects on levels of acetyl-CoA and ATP, from oxidative damage associated with the increased activity of the SSAT/APAO pathway, and the increased metabolic flux through the polyamine pathway. This flux is increased due to the futile cycle set up by compensatory increases in polyamine synthesis in response to constitutively elevated SSAT. Levels of SSAT needed to bring about these changes are not normally seen under physiological conditions since the decline in polyamines resulting from increases in SSAT removes the stimulus for continued SSAT expression. However, some polyamine analogues, which are not SSAT substrates and are metabolized relatively slowly, are also potent promoters of SSAT induction and their toxicity/therapeutic effects may be related to prolonged elevation of SSAT (section 11.1). There is also an active transport system for the uptake of polyamines that may contribute to the control of polyamine content. Although details of this system are still subject to discussion,68−70 it is well established that it is responsive to the intracellular polyamine content and is greatly reduced in activity when cellular polyamine levels are high. This regulation is mediated by antizyme. It is also likely that polyamine content is affected by the activity of the catabolic oxidases described below. Although direct proof that changes in oxidase activity play a role in controlling polyamine levels under normal physiological conditions is lacking, it is likely that alterations in the availability of their substrates and/or the possible induction or release of oxidases during infections, exposure to chemicals, and other pathophysiological insults cause increased polyamine degradation through these catabolic enzymes.

5. POLYAMINE METABOLISM AND HOMEOSTASIS As might be expected from the outlines of essential polyamine functions and the toxicity of excess polyamines described above, the content of polyamines is very highly regulated. Regulation occurs at multiple steps, of which the most important appear to be changes in the activity of a polyamine transport system and of three enzymes: ODC; S-adenosylmethionine decarboxylase (AdoMetDC); and spermidine/spermine-N1-acetyl transferase (SSAT, Figure 3). Both ODC and AdoMetDC are negatively regulated by polyamines so that activity is reduced when spermidine and spermine levels are high. Changes in ODC activity are brought about by alterations in the content of enzyme protein, which is controlled at the levels of transcription, mRNA stability, translation, and protein turnover. A protein termed antizyme, which is increased when polyamine levels are high, is of critical importance in regulating ODC. It does so by binding to the protein and causing its proteasomal degradation.50−52 Similarly, the content of AdoMetDC, which is formed as a proenzyme that undergoes autocatalytic cleavage to form its pyruvoyl cofactor and its two subunits,13,53 is also varied in response to polyamines. Transcription of the AdoMetDC gene is inhibited via a polyamine-responsive element;54 translational regulation occurs via small open reading frames in the 5′ UTR at which ribosomes stall in a manner altered by polyamine content;55,56 and AdoMetDC protein degradation is increased when polyamine levels are high.54,57 Activation of AdoMetDC is brought about by putrescine, which increases the rate of processing and the catalytic activity in mammals, yeast, and some other organisms.13,53,58 This activation allows extensive conversion of putrescine into spermidine in these species. In trypanosomes, an activating protein termed prozyme replaces putrescine in increasing AdoMetDC activity.59 The third key enzyme in maintaining polyamine homeostasis is SSAT.37,60−62 SSAT adds acetyl groups to the aminopropyl end(s) of spermidine and spermine (Figure 3). This acetylation reduces the charge on the polyamines, thus altering their ability to bind to acidic macromolecules, rendering them more susceptible to excretion from the cells and making them substrates for acetylpolyamine oxidase (APAO), which forms N-acetyl-3-aminopropanal and a smaller polyamine, effectively reversing the biosynthetic reactions (see section 6.3). SSAT is normally present in very low amounts but is very highly regulated and is highly inducible by polyamines.51,62 The regulation of SSAT protein content occurs at multiple levels including transcription, mRNA processing, mRNA translation, and protein stabilization.51,62−64 In the presence of high levels of polyamines, transcription and translation of SSAT mRNA are increased, whereas incorrect splicing of the SSAT mRNA and degradation of the SSAT protein are reduced. These changes can lead to very large and rapid increases in SSAT protein and in the formation of the acetylated forms of spermidine and spermine that are then rapidly converted back to putrescine or excreted. These products pass more readily through the cell membrane than the highly charged polyamines, and their excretion may be facilitated by a polyamine efflux system.65

6. OXIDASES ATTACKING POLYAMINE A variety of oxidases are known that can degrade polyamines.71−74 Some of these such as diamine oxidase and a serum amine oxidase have been known for almost a hundred years. Others such as spermine oxidase (SMO) were discovered only in the past decade. This review will focus on oxidases present in mammalian tissues. (There are several useful reviews on the plant and yeast polyamine oxidases and the molecular evolution of the family of polyamine oxidases.23,75−78) Unfortunately, the nomenclature of these enzymes is confusing The mechanistic aspects of amine oxidation are well understood, and they are best characterized in terms of their cofactors and preferred substrates. Detailed mechanistic and structural studies have shown that these oxidases can be classified as Cu2+-containing and FAD-requiring. Both generate H2O2. New assays with techniques clearly identifying the reaction products and specific substrates are a promising way to provide specific measurements of individual oxidases.79 These assays, combined with the use of specific antisera, should aid in finding the distinction and relative importance of polyamine oxidases. 6.1. Diamine Oxidase. Diamine oxidase is a Cu2+dependent oxidase that acts on histamine and a variety of diamines including putrescine.80,81 The products of putrescine oxidation are H2O2, ammonia, and Δ1-pyrroline formed by the 1786



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Figure 4. Reactions of mammalian oxidases catabolizing diamines and polyamines. (A) Diamine oxidase. The reaction with putrescine is shown. Diamine oxidase has many other substrates including histamine. (B) Serum polyamine oxidase. Other Cu2+-dependent oxidases produce similar products from spermidine and spermine. (C) Acetylpolyamine oxidase (APAO). (D) SMO. Yeast Fms1 catalyzes the same reaction.

cyclization of the aldehyde product, 4-aminobutanal (Figure 4A). This cyclization limits any potential toxic effects of the

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acetylated substrates.95,99 Importantly, it is not located in peroxisomes, and some splice variants may have a nuclear location.51,100 Therefore, its products may be more likely to damage DNA. SMO is normally present in mammalian cells at low levels with the possible exception of the brain.101 This may account for the delay in its discovery, which actually occurred as a result of cloning sequences likely to be polyamine oxidases. However, it is highly inducible by a variety of stimuli including polyamine analogues having antitumor activity.51,94,97,102,103 Some of these studies are based only on indirect measurement of transcripts or immunoreactive material rather than the specific assay of enzymatic activity. Improved assays for the enzyme will be valuable in the accurate determination of the actual capacity to degrade spermine.98 Yeast contains an SMO named Fms1. The 3-aminopropanal formed by Fms1 is further oxidized to produce β-alanine, which is necessary for the biosynthesis of pantothenic acid. The crystal structures of this enzyme and that of a maize polyamine oxidase are available.104,105 Their similarity in primary structure to SMO and the good understanding of the enzymatic mechanism of these enzymes97,99 should be useful in the development of specific, potent inhibitors of SMO. These would be extremely valuable to clarify its function.

oxidase reaction on putrescine exert significant cellular effects. Diamine oxidase has only poor activity toward spermidine and even less ability to attack spermine.82,83 However, a number of other Cu2+-dependent oxidases with various specificities that include the ability to attack the higher polyamines have been isolated from mammalian sources and are described in section 6.2. 6.2. Serum Amine Oxidase and Related Enzymes. Ruminants and some other animals contain a serum amine oxidase.84,85 This is also a Cu2+-dependent oxidase, and it attacks both spermidine and spermine at the terminal aminopropyl N atoms to form amino aldehydes, H2O2 and ammonia (Figure 4B).84,86 These aldehydes are reactive and likely to be toxic, but they also spontaneously decompose undergoing β-elimination to form the highly toxic acrolein (section 8.1). It should be noted that the presence of serum amine oxidase is species specific, and the potential importance of this enzyme in humans, which are not good sources of the enzyme, is not fully established. However, several other amine oxidases that can attack the higher polyamines and diamines at the terminal amino groups have been described. There is a rise in such a human polyamine oxidase activity in blood during pregnancy.72,87 The resulting toxic products may affect the immune system and contribute to the protection of the fetus from maternal immune rejection. A “diamine oxidase” that can degrade spermine was purified from human seminal plasma,48 and a Cu2+-dependent oxidase has been isolated from mitochondria.88 This enzyme does attack spermine and spermidine and a variety of other amines including agmatine. Its function is unknown, but it may be involved in the development of apoptosis. The Cu2+-dependent amine oxidases, including diamine oxidase, are strongly, but nonspecifically, inhibited by aminoguanidine and related compounds. Aminoguanidine has been widely used experimentally to prevent these enzymes from degrading polyamines.89 6.3. Acetylpolyamine Oxidase (APAO). A major constitutive oxidase that acts on mammalian polyamines was first isolated in 1977.90 It has been cloned and more completely characterized using the recombinant enzyme.91−93 Early studies on this enzyme showed that it acted on spermidine and spermine and that it was described as polyamine oxidase. However, the ability to attack these substrates required the addition of benzaldehyde (which forms a Schiff base with the substrate), and subsequent studies showed that its natural substrates were N1-acetylated polyamines with a strong affinity for N1-acetylspermine and N1-acetylspermidine and little or no activity on spermine.91,93 The products are H2O2, N-acetyl-3aminopropanal, and spermidine or putrescine depending on the substrate (Figure 4C). It is therefore more accurately described as acetylpolyamine oxidase (APAO). APAO is a member of the monoamine oxidase family of flavoproteins. It contains a peroxisomal signaling sequence and is localized to peroxisomes. This may minimize the potential toxicity of the H2O2 formed. The controlling factor in the degradation of polyamines by APAO is SSAT because little or no acetylated polyamine substrates are present in the absence of SSAT induction. 6.4. Spermine Oxidase (SMO). Another member of the flavoprotein amine oxidase family was identified in 2001 by Casero and colleagues.94 It acts on spermine generating spermidine, 3-aminopropanal, and H2O2 (Figure 4D).95−98 Although SMO has some primary structural similarity to APAO, it does not act on spermidine and does not require

7. OVERALL ROLE OF OXIDASES IN CONTROLLING POLYAMINE CONTENT Application of inhibitors of diamine oxidase such as aminoguanidine does lead to an increase in putrescine but has little effect on the polyamine content. At present, there are no highly specific and potent inhibitors of the individual polyamine oxidases. Most studies aimed at blocking polyamine oxidation by the FAD-dependent oxidases have used N1,N4-bis(buta-2,3dienyl)butanediamine (MDL72527), which was originally developed to inactivate APAO.106−108 MDL72527 is a potent irreversible inhibitor, but more recent studies have shown that this drug and closely related inhibitors also inactivate SMO and serum polyamine oxidases.94,99,109−111 MDL72527, although relatively nontoxic, causes a build up of spermine, which can reach toxic levels if the inhibitor treatment is prolonged.112 These experiments confirm the potential toxicity of spermine when the catabolic pathways are inactivated, but studies with more specific inhibitors or the use of other techniques such as siRNA or gene knockouts are needed to provide data that more definitively implicates one or other of these oxidases. There was no increase in SMO activity in transgenic mice that greatly overexpress the spermine synthase gene from a powerful ubiquitous promoter.17,113 It is possible that the SMO and SSAT/APAO pathways provide redundant means to prevent excess polyamine accumulation. Recent development of mice with the deletion of the gene encoding SMO and/or APAO should help to clarify this question. There is no doubt that high levels of SSAT produced by application of inducers or transfection with constructs expressing the SSAT gene cause a massive reduction of polyamine content.62,66,67 This is consistent with the oxidation of the acetylation products by APAO, and this conclusion has been reached in many studies. However, these acetylation products can be excreted from the cell, and this also contributes to the fall in polyamines and could be critical in some cell types. For example, breast cancer cells treated with polyamine analogues that induce both SSAT and SMO showed growth 1788



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Figure 5. Production of acrolein by β elimination from polyamine oxidation products.

and 73), many recent studies have confirmed the pioneering experiments of Kimes and Morris showing that, at low concentrations similar to those generated in the enzymatic oxidation reactions, acrolein is the key toxic intermediate from polyamine catabolism.117,118 Acrolein can also be formed spontaneously from the SMO product 3-aminopropanal with the elimination of ammonia (Figure 5).120,121 The extent to which this conversion occurs in a cellular context, where enzymatic reduction or the direct reaction with cellular components provides alternate routes to its disposition, is not yet fully established. However, as described below, there is good evidence of the production of acrolein under conditions where SMO is active. The production of acrolein from Nacetyl-3-aminopropanal has also been proposed, but this seems unlikely, and the absence of toxicity of APAO to cells to which acrolein was extremely toxic122 argues strongly against this. Protective effects against acrolein include the reaction with glutathione forming 3-hydroxypropyl mercapturic acid.123−125 Acrolein generated by serum oxidases from polyamines induces phase 2 enzymes including glutathione-S-transferases that may then limit the toxic effects.126 This induction is mediated via the increase in nuclear Nrf-2, which then activates genes containing an antioxidant response element. The production of GSH itself is also stimulated by acrolein via a c-Jun and nuclear factor κB (NF-κB) mediated pathway.127 Recently, it has been shown that exposure to acrolein leads to the induction of interleukin-6 and C-reactive protein, which exert protective functions in brain cells.128,129 Accumulation of 3-aminopropanal in lysosomes causes toxic effects, which are more prominent in cells lacking the endosomal/lysosomal membrane protein NPC1 whose deficiency causes a form of Niemann-Pick C disease.130 3Aminopropanal showed significant toxicity to rat ganglion cell cultures, although much less of that of acrolein and H2O2.122 However, the N-acetyl-3-aminopropanal generated by APAO was not toxic to these cells. Both aldehydes are readily

inhibition, and the loss of polyamines although APAO was not detected.114 Reduction of either SSAT or SMO using siRNA reduced the toxicity observed. The results show clearly the potential importance of the elevation of SSAT and SMO in these cells. In other cell types that do contain significant levels of constitutive APAO, the oxidation by this enzyme should also contribute to the fall in polyamines and consequent effects on cell growth.

8. TOXICITY OF POLYAMINE OXIDATION PRODUCTS Clearly, the oxidative catabolism of polyamines leads to a variety of unstable and potentially toxic products. All of these are known to exert cytotoxic effects on bacteria, viruses, and tumor cells,44,71 but major differences in potency occur as a result of a number of factors including their reactivity; their site of generation; the activity of detoxifying mechanisms; and differences in ability to damage cellular targets. 8.1. Polyamine Derived Aldehydes Including Acrolein. The aldehydes formed as a result of the oxidation of polyamines have significant potential to direct toxic effects. This can be modified by metabolic detoxification such as the reactions of aldehyde dehydrogenases115 and by nonenzymatic reactions that can either limit the reaction with cellular components (for example, the cyclization of 4-aminobutanal) or enhance such reactions (for example, the formation of acrolein from terminally oxidized spermine or spermidine). The production of acrolein by β elimination from the products of the plasma amine oxidase reaction, N′-(4aminobutyl)-aminopropionaldehyde and N,N′-bis(3-propionaldehye-1,4-butanediamine) (Figure 5), and its potential role in their toxicity were reported more than 40 years ago.84,116−119 The importance of acrolein formation as a major factor in the toxicity of terminally oxidized polyamines was strongly supported by studies of the kinetics of the inhibition of bacterial macromolecular synthesis by spermine in the presence of serum amine oxidases.118 Although there are a few claims disputing the role of acrolein formation (discussed in refs 72 1789



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converted to the nonreactive β-alanine or its acetylated derivative by aldehyde dehydrogenases. 8.2. Reactive Oxygen Species. H2O2 is potentially highly damaging to cells as a source of reactive oxygen species. Low levels of H2O2, particularly those generated in peroxisomes, are efficiently dealt with by catalase. This may limit any damage via the APAO reactions, but, as discussed extensively by Casero and collaborators, induction of SMO may be a more important source of H2O2 mediated damage leading to cytotoxicity and possibly to DNA damage and the initiation of cancer.114,131,132 The nuclear location of some forms of SMO may be of particular relevance in generating oxidative damage from H2O2 to DNA.100 Polyamines, particularly spermine, are effective as protective agents against reactive oxygen species in microorganisms, plants, and mammals (section 9). Therefore, any reduction in polyamine content brought about by oxidative catabolism may enhance the potential damage due to the reactive oxygen species generated by the catabolic reactions.

mediated via the reduction of translocation of NF-kB p65 into the nucleus and phosphorylation of phosphoinositide-3kinase and mitogen activated protein kinases.154 Spermine and to a lesser extent spermidine were able to block phorbol esterinduced inflammation and macrophage activation in mouse skin via similar effects.155 9.1. Glutathionylspermidine and Trypanothione. The role of glutathione in defense against oxidative stress and in protection of mammals from infection by microbes is well established.156,157 Reduced glutathione maintains a reduced cellular environment, and its thiol acts as a nucleophile in reactions with both exogenous and endogenous electrophilic species. The conjugation of a large proportion of the cellular spermidine with glutathione forming N1-glutathionylspermidine (Figure 1) during prolonged anaerobic incubation of E. coli cultures was first reported in 1970.158,159 Recent work has shown that the gss gene that encodes glutathionylspermidine synthetase is restricted to certain Eubacteria and kinetoplastids.160 Deletion of this gene did not affect normal aerobic growth but led to a significant change in the gene expression patterns. Although the function of N1-glutathionylspermidine is still unknown, it is likely to play a role in survival in conditions of high cell density and low aerobic stress, where the antioxidant effects of polyamines and glutathione are not required. In 1985, it was discovered that trypanosomes do not use glutathione but instead require N1,N8-bis(glutathionyl)spermidine (termed trypanothione; Figure 1) as a cofactor for trypanothione reductase, which replaces glutathione reductase.161 This has led to intense interest into the role of trypanothione in parasite growth and the importance of polyamines as the precursor of trypanothione. Trypanothione is unique to trypanosomatids. If these parasites are unable to synthesize it due to mutations, gene manipulation, or treatment with drugs, they fail to survive.162−164 The inability to form trypanothione may contribute to the proven usefulness of ODC inhibitors as agents for the effective treatment of certain types of African sleeping sickness.165−167 Although no drugs have yet been placed into clinical use, the enzymes trypanothione synthase and trypanothione reductase are particularly attractive candidates for the synthesis of antitrypanosomal drugs since there is no mammalian equivalent, and the host cells neither synthesize nor require trypanothione.162,164,168−171

9. PROTECTIVE EFFECTS OF POLYAMINES AGAINST OXIDATIVE STRESS AND INFLAMMATION The capability of polyamines to slow autoxidation in living cells is long-established.43 The ability to quench singlet molecular oxygen and to protect phage DNA from it was initially reported by Khan and colleagues.133,134 Spermine prevented DNA strand breakage in phage exposed to an oxygen radical generating system using H2O2 and a transition metal.135,136 Putrescine and spermidine protect E. coli from oxidative stress resulting from exposure to H2O2,137 paraquat,138,139 superoxide,140 and antibiotics.141 This protection is mediated both via the ability of these polyamines to stimulate the synthesis of protective gene products137,142 and from direct effects limiting DNA damage.138,140 A mutant strain of S. cerevisiae that lacks a functional gene encoding AdoMetDC and is therefore unable to synthesize spermidine and spermine died rapidly when incubated in 95% O2 or air.143,144 The toxicity and rise in reactive oxygen species were prevented by expressing superoxide dismutase or by spermine addition to the cultures. The strain used also lacked the gene encoding Fms1, so spermine could not be converted to spermidine. These results confirm a role for spermine in protection from oxidative damage. Such protection may also alleviate cadmium induced toxicity mediated via reactive oxygen species in red algae.145 The binding of polyamines to phospholipid membranes protects against lipid peroxidation and oxidative stress.146,147 Both spermidine and spermine are active in protection from H2O2,148,149 but studies using cultured fibroblasts manipulated to contain only one of the polyamines showed that spermine was more effective.149 Depletion of glutathione further increased the toxicity indicating that polyamines play a distinct role in protection from reactive oxygen species from that played by glutathione.149 The antioxidant activity of polyamines also provides embryonic protection from dysmorphogenesis due to hyperglycemia150 and from aldehyde mediated anticoagulant effects.151 Polyamines have significant anti-inflammatory effects in addition to acting as antioxidants.152 Spermidine and spermine administered prior to treatment with a lipopolysaccharide irritant reduced the formation of NO and prostaglandin E2 via down-regulation of their biosynthetic enzymes and reduced synthesis of IL-6 and TNF-α.153−155 These effects were

10. PATHOPHYSIOLOGY ASSOCIATED WITH POLYAMINE OXIDATION Increased exposure to polyamine oxidation products is a contributory factor to the development of many serious chronic and acute diseases. The majority of the polyamine in the cell is bound to negatively charged macromolecules including membrane components, nucleic acids, and proteins. Tissue damage can lead to the release of polyamines from these sites and to a rise in the free polyamine content. This in turn activates the catabolic oxidative pathways with the production of the toxic products described above. Other insults such as infections can induce the oxidases directly with the same results. Cell death can result in the extracellular release of polyamines and their metabolic enzymes exacerbating the damage. 10.1. Stroke and Neurological Diseases. There is convincing evidence based on studies with cell cultures, laboratory rodents, and human patients that oxidative 1790



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metabolic profiling of significant changes in polyamine content in Alzheimer’s disease.184 The possible importance of SMO in producing oxidative stress leading to neurotoxicity has been supported by studies showing that the HIV-1 Tat gene product increases SMO activity in human neuroblastoma cells and that this increase reduces cell viability.185 The Tat-induced SMO activation was blocked by an NMDA receptor antagonist, and pretreatment of cells with N-acetylcysteine was able to restore cell viability. These results are consistent with an important role for SMO mediated oxidative stress in the pathogenesis of HIVassociated dementia. The human studies indicating the potential importance of acrolein derived from polyamines in neurological damage have been supported by experiments with rodents.182,186,187 A mouse model with a photochemically induced infarction showed that protein conjugated acrolein was greatly increased and that tissue polyamine content decreased within 24 h. Increases in the content of protein conjugated acrolein, polyamines, and polyamine oxidases in plasma were also seen. The treatment caused RNA damage, which could lead to polyamine release from bound sites and their oxidation. The importance of acrolein or reactive oxygen species in initiating this damage was supported by the ability of N-acetylcysteine to reduce the infarct size. Further examination of this model system showed that the increase in acrolein conjugated albumin was much larger than that of 8-hydroxyguanine in DNA (a measure of damage due to reactive oxygen species including H2O2) and 4-hydroxynonenal conjugated albumin (a measure of lipid peroxidation).187 Treatment with MDL 72527 to block both SMO and APAO reduced the infarct volume and the rise in their metabolites, supporting the role of polyamine oxidases in brain damage. Critically, the importance of the production of acrolein from spermine was demonstrated by using Gy mice, which have no spermine due to the deletion of the spermine synthase gene.17 The infarct volume and level of acrolein conjugates was lower in these mice.187 Spermidine content is significantly increased in Gy mice, and this result therefore confirms the importance of spermine as the source of acrolein and focuses attention on SMO. Overall, these studies provide convincing evidence for increased acrolein and subsequent reaction with proteins as a correlate of brain damage. Acrolein can be generated via multiple pathways including lipid peroxidation and is also present in cigarette smoke and as an environmental contaminant. However, acrolein production from arachidonic acid was very low compared to production from spermine.129,181,182 The hypothesis that polyamine oxidases could generate acrolein and that this acrolein may be responsible for neurological cell damage is compelling. However, clear evidence that SMO is increased prior to a stroke-initiating event in humans is not yet available. The initial event causing extracellular release of SMO is not known, and it is not clear why the presence of SMO in the plasma should produce extensive polyamine oxidation since plasma levels of polyamines are very low and mainly confined to blood cells. It is possible that polyamine transfer to extracellular sites is secondary to tissue damage. The same arguments apply to APAO release; although its acetylated substrates are more readily lost from the cell after SSAT induction, its products do not readily form acrolein. It remains possible that some other Cu2+-containing oxidases that produce terminally oxidized

metabolites derived from polyamines may be involved in neuronal damage.122,172,173 Treatment with MDL 72527 to block polyamine oxidases reduced ischemic injury after surgical occlusion in spontaneously hypertensive rats174,175 and in a model of traumatic brain injury caused by cortical impact.176 The treatment also reduced the increase in putrescine and increased N1acetylspermine levels at the lesion site. The reduction in putrescine accumulation is consistent with inhibition of the SSAT/APAO pathway, but the conclusion from this work that APAO is a critical target175 needs to be reevaluated in light of later findings that SMO is also blocked by MDL 72527. Indeed, both SSAT and SMO mRNA levels and immunoreactivity were elevated in the brain after cortical impact injury.177 Occlusion of the cerebral artery in rats was reported to increase polyamine oxidase activity and lead to the production of 3-aminopropanal.178 Oxidase activity was measured using spermine as a substrate, and it seems likely that SMO was responsible since APAO does not produce 3-aminopropanal or act significantly on spermine. 3-Aminopropanal had toxic effects in glioma cells including lysosomal rupture, caspase activation, and apoptotic cell death. Treatment with N-(2mercaptopropionyl)glycine, to neutralize 3-aminopropanal by forming a nontoxic thioacetal adduct, reduced these toxic effects in glioma cells179 and protected rats from infarcts after cerebral occlusion.180 This work was extended to humans suffering aneurysmal subarachnoid hemorrhage where increased levels of 3-aminopropanal modified protein levels correlated with the degree of cerebral injury.180 This work suggests a role for the reactive aldehyde 3-aminopropanal adducts in brain injury, but it is also consistent with the work described below in which acrolein derived from 3-aminopropanal is the critical intermediate.177 Igarashi and colleagues have provided convincing evidence that measurement of APAO and SMO proteins and acrolein adducts is a potentially useful marker for patients suffering strokes.173,181,182 Measurements of plasma samples from stroke patients showed an increase in acrolein levels and in the content of APAO and SMO (measured by ELISA assays with specific antibodies). These increases were correlated with the size of the infarct. Plasma levels of the normally intracellular oxidases rose after strokes with the increase in APAO preceding that of SMO. Acrolein content increased following the release of these oxidases. Importantly, these changes were seen in patients who had only moderate symptoms and required MRI analysis to confirm the presence of brain damage.181 Further studies have shown that silent brain infarctions can be detected by measuring a rise in the plasma levels of protein conjugated acrolein, interleukin-6, and C-reactive protein.128 Surprisingly, however, the urinary content of 3-hydroxypropyl mercapturic acid, an acrolein−glutathione metabolite, actually decreased in stroke patients, and the levels were inversely correlated with severity.125 Since acrolein toxicity is known to be counteracted by reaction with glutathione and glutathione synthesis is increased in acrolein treated cells,127 it was suggested that stroke is aggravated when the nervous system tissues have a reduced level of glutathione.125 Recently, this work has been extended to Alzheimer’s disease.183 Increases in protein conjugated acrolein were observed in patients with mild cognitive impairment and in confirmed disease. When combined with amyloid-β Aβ40/ Aβ42 ratios, the acrolein measurements provided a potentially useful biochemical marker. There is other evidence from 1791



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hibitors of cyclin dependent kinases decreased polyamine levels via upregulation of APAO and SMO in HCT 116 cells.203 Inhibition of these enzymes or their induction decreased the apoptosis produced by cyclin dependent kinase inhibitors on HCT 116 cells. Interference with the apoptotic pathway may reinforce the carcinogenic stimulus produced by oxidative stress. 10.4.1. Prostate Cancer. High levels of SMO as measured by immunostaining were found in tissues from patients diagnosed with prostate cancer and prostatic intraepithelial neoplasia.204 Since the incidence of prostate cancer has been related to persistent inflammation,205 these observations suggest that spermine metabolism may be a potential source of cancer initiation. The prostate is a rich source of polyamines, and spermine is present in high levels in prostatic secretions. Earlier work based on its effect on the growth of prostatic cancer cells in culture suggested that this spermine might be an endogenous inhibitor of prostate cancer development.206 Unless high concentrations of spermine were added, this effect was inhibited by aminoguanidine, suggesting that the artifactual generation of oxidation products by serum oxidases could be responsible. However, more detailed follow up using serum free medium for the growth of rat prostate carcinoma cells implicated the induction of the ODC regulatory protein antizyme in the ability of spermine to reduce cell growth.207,208 SMO could therefore act both by reducing the protective effect of spermine and generating oxidative damage. In contrast to these results, overexpression of SSAT in LNCaP prostate carcinoma cells or in a mouse TRAMP model of prostate cancer actually reduced cell growth and tumor incidence.209,210 This result of SSAT expression differs from that found in skin cancer studies where increased SSAT enhanced tumor growth and development (see section 10.4.3). One probable explanation for the difference is that the huge induction of SSAT in the transgenic model used for prostate studies led to greatly increased metabolic flux through the polyamine pathway reducing acetyl-CoA, S-adenosylmethionine, and ATP levels. The more modest changes in SSAT levels in the skin do not bring about this derangement in metabolism that could have profound antiproliferative effects. 10.4.2. Gastrointestinal Cancers. Infection with Helicobacter pylori is linked to peptic ulcer disease, chronic gastritis, and gastric cancer. SMO has been implicated in the etiology of these changes. Infection with H. pylori causes an increased synthesis of polyamines via the induction of ODC and of arginase II, generating its substrate ornithine.211,212 This increase in spermine may actually interfere with the immune response to such infection by inhibiting inducible NO synthase and NO production,212 but this effect was abrogated by SMO induction.213 SMO was induced when macrophages or human gastric epithelial cells were infected with H. pylori.214−216 The resulting oxidative stress causes apoptosis of macrophages and DNA damage in gastric cells that increases the probability of cancer development.217 This damage was prevented by the use of MDL 72527, catalase, or expression of a siRNA targeting SMO. The microbial oncoprotein cytotoxin associated gene A (CagA) may mediate H. pylori induced gastric carcinogenesis. Only cagA(+) H. pylori strains led to the induction of SMO and the production of gastric epithelial cells with oxidative DNA damage. It was also observed that a subpopulation of these cells were resistant to apoptosis leading to a high risk for malignant transformation.218,219

polyamines that can lead to acrolein are activated or released by tissue damage. A recent transgenic mouse model in which SMO is overexpressed in the neocortex should be a useful experimental system to examine the importance of SMO in neurotoxicity.101 Initial studies showed that there was an increase in oxidative stress in the neocortex and that the mice were more sensitive to brain injury by kainate than controls. 10.2. Renal Failure. Polyamines or their oxidation products were first postulated to be significant contributors to uremic toxins by Campbell and colleagues.188,189 More recent detailed studies have focused on oxidation products as mediators of toxicity in patients with chronic renal failure.173,190−193 Both free and protein conjugated acrolein were increased in the plasma of patients with chronic renal failure and in a variety of kidney diseases including diabetic nephropathy, chronic glomerulonephritis, and nephrosclerosis.190,191 The accumulation of polyamines in blood due to the decrease in their excretion into urine in uremia and the release of polyamines and oxidative enzymes after renal damage may form a combination, exacerbating disease. Polyamines and acrolein inhibited renal organic cation transporters.193 SSAT and SMO increase in kidneys subjected to injury after endotoxin or ischemia-reperfusion, and the resulting activation of polyamine catabolism is associated with oxidative DNA damage.194,195 Mice with the SSAT gene inactivated were more resistant to ischemia-reperfusion.196 10.3. Liver Damage. A similar role for SSAT has been proposed for the development of ischemia-reperfusion injury in the liver.196 SSAT induction was also implicated in the development of liver damage after exposure to carbon tetrachloride.197 The massive induction of SSAT by carbon tetrachloride is well established,60,62 and it is likely that the resulting decline in spermine caused by the SSAT/APAO pathway enhances the oxidative damage from polyamine catabolism. The ethanol metabolite acetaldehyde induced SMO and increased acrolein levels in hepatic cells.198 Prevention of the induction using siRNA reduced the toxicity of acetaldehyde. These results provide preliminary evidence that polyamine oxidation may be involved in the hepatotoxicity associated with alcohol consumption. This conclusion is consistent with other studies showing a reduction in polyamine content after ethanol and protection from its antiproliferative action by provision of polyamines.199 10.4. Inflammation and Cancer Initiation. Oxidative stress is well established as a potential carcinogenic stimulus causing promutagenic DNA damage, stimulating cell proliferation and interfering with critical defense mechanisms. The production of reactive oxygen species, reactive aldehydes, and reduction in the content of potentially protective polyamines due to polyamine oxidation are therefore a highly plausible route for the development of neoplasia that has been the subject of several comprehensive reviews.51,131,132,200 Numerous stimuli leading to cancer cause increases in oxidative polyamine catabolism as described for specific tissues below. More generally, induction of SMO leading to reactive oxygen species was shown to be a consequence of the production of tumor necrosis factor-α (TNF-α) or interleukin-6 in human lung bronchial epithelial cells.201 TNF-α also causes NF-κB mediated increase in SSAT expression and consequent loss of polyamines and production of H2O2 and Nacetyl-3-aminopropanal via the SSAT/APAO system.202 In1792



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particles.240 It remains to be established whether regimes for delivery to provide a clear therapeutic benefit with acceptable toxicity can be moved into clinical practice.

The bacterium enterotoxigenic Bacteroides f ragilis produces chronic inflammation and has been implicated as a risk factor for colorectal cancer. Purified B. fragilis toxin increases SMO in colonic epithelial cells, and induction of colitis with B. f ragilis in C57BL/6 mice is associated with increased SMO expression.220 Treatment with MDL 72527 reduced chronic inflammation and proliferation. Additional studies using the multiple intestinal neoplasia (Min) mouse model showed that the inhibitor significantly decreased colon tumorigenesis induced by B. f ragilis.220 Comparisons of frozen biopsy samples showed that SMO mRNA content and SMO immunoreactivity were increased in mononuclear inflammatory cells from patients with ulcerative colitis, an inflammatory condition known to impart a high risk of colorectal cancer.221 10.4.3. Skin Cancer. Transgenic mice overexpressing SSAT in the skin by virtue of a keratin 6 promoter were more sensitive to tumor induction by a two-stage tumorigenesis protocol using initiation with 7,12-dimethylbenz[a]anthracene and promotion with 12-O-tetradecanoylphorbol-13-acetate.222 The increased tumor incidence was partially prevented by treatment with MDL 72527, which prevented degradation of the acetylated polyamines.223 This finding is consistent with the hypothesis that reactive oxygen species and aldehydes liberated by the SSAT/APAO pathway may enhance tumor development.

12. CONCLUSIONS The studies reviewed in section 10 provide a convincing case for the possible involvement of oxidative polyamine catabolism in the development of a wide range of diseases. Many of these conditions are likely to have a complex etiology, and the extent to which polyamine metabolites contribute to them still remains to be established and will require both animal studies and human correlations. It will be important to use specific inhibitors of the relevant oxidases (which are still under development but should be obtainable with the extensive knowledge of the structure and mechanism of these enzymes) and mice with gene deletions of the key enzymes for such studies. Such inhibitors (or activation of pathways detoxifying the active intermediates from polyamine degradation) could have significant potential for disease prevention. However, a cautionary note for such development is raised by a series of papers that suggest that polyamine oxidation may be an important means of generating required apoptosis during embryonic development and tissue renewal.241−243 It remains to be seen whether inactivation of the catabolic pathways can be used with sufficient safety to provide therapeutic chemoprotection.

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11. POTENTIAL THERAPEUTIC IMPLICATIONS OF POLYAMINE OXIDATION 11.1. Polyamine Analogues. A wide variety of polyamine analogues with N-terminal substitutions have been proposed as antiparasitic agents and antitumor agents on the basis of promising studies with tumor cell cultures and tumor xenografts in immunocompromised mice, and some analogues have reached clinical trials.224−226 Despite intense interest and numerous publications, the basis for the activity of these analogues is still unclear. The original explanations were that they (a) bind to critical sites normally occupied by polyamines but fail to produce the normal and essential polyamine mediated functions and that (b) in some cases, they cause activation of the SSAT/APAO or SMO degradative pathways, thus reducing normal polyamine content needed for cell growth. It seems very likely that the antitumor action of these analogues is also related to the ability of the activated oxidative catabolism to cause sufficient cytotoxicity via the pathways described in section 8 and by virtue of the fact that APAO and SMO cleave many of these analogues releasing H2O2, an aldehyde, and a polyamine not normally found in the cell.227−232 11.2. Possible Use of Polyamine Oxidase and a Polyamine Substrate for Therapy. The polyamine catabolic pathway has been proposed as a potential therapeutic as a result of its antimicrobial, antiviral, antiproliferative, and antineoplastic effects.233−235 The oxidation products derived from the action of polyamine oxidases may exert such effects, and these could be enhanced by the reduction in the content of the polyamines themselves. Multiple studies have shown that the application of bovine serum oxidase and spermine can kill tumor cells either alone236,237 or in combination with radiation.238 Conjugation of the oxidase with a biocompatible hydrogel polymer increased the effectiveness of this treatment.239 Another suggested approach involves linking the enzyme to fluorescent and magnetically drivable nano-

AUTHOR INFORMATION

Corresponding Author

*Department of Cellular and Molecular Physiology, Room C4739B, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, P.O. Box 850, 500 University Drive, Hershey, PA 17033, USA. Phone: 717-5318152. E-mail: [email protected]. Notes

The author declares no competing financial interest.

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ABBREVIATIONS ODC, ornithine decarboxylase; AdoMetDC, S-adenosylmethionine decarboxylase; SSAT, spermidine/spermine-N1-acetyl transferase; APAO, acetylpolyamine oxidase; SMO, spermine oxidase; siRNA, small interfering RNA; TNF-α, tumor necrosis factor-α; NF-κB, nuclear factor κB

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REFERENCES

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Toxicity of Polyamines and Their Metabolic Products - ACS Publications

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