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PubMed2005

Polyamine transport in parasites: a potential target for new antiparasitic drug development.

The metabolism of the naturally occurring polyamines-putrescine, spermidine and spermine-is a highly integrated system involving biosynthesis, uptake, degradation and interconversion. Metabolic differences in polyamine metabolism have long been considered to be a potential target to arrest proliferative processes ranging from cancer to microbial and parasitic diseases. Despite the early success of polyamine inhibitors such as alpha-difluoromethylornithine (DFMO) in treating the latter stages of African sleeping sickness, in which the central nervous system is affected, they proved to be ineffective in checking other major diseases caused by parasitic protozoa, such as Chagas' disease, leishmaniasis or malaria. In the use and design of new polyamine-based inhibitors, account must be taken of the presence of up-regulated polyamine transporters in the plasma membrane of the infectious agent that are able to circumvent the effect of the drug by providing the parasite with polyamines from the host. This review contains information on the polyamine requirements and molecular, biochemical and genetic characterization of different transport mechanisms in the parasitic agents responsible for a number of the deadly diseases that afflict underdeveloped and developing countries.

Animals↗

PubMed2005

Oxidative metabolites are involved in polyamine-induced microglial cell death.

Pathological activation of microglia, which reside quiescently in physiological CNS, is associated with various neurodegenerative diseases. Endogenous polyamines, spermidine and spermine, are known to be activators of cell proliferation and differentiation. We previously reported that both spermidine and spermine induce dose-dependent cell death in cultured rat brain microglia at a submicromolar concentration range via apoptotic process, whereas cultured astrocytes were less sensitive to these polyamines [Neuroscience 120 (2003) 961]. These polyamine effects were observed only in the presence of fetal bovine serum. In the present study we examined further the mechanism of polyamine-induced microglial cell death. Amine oxidase in fetal bovine serum produces hydrogen peroxide and an aminoaldehyde from spermine, and the latter generates acrolein spontaneously. Acrolein was found to be much more toxic to microglia than to astrocytes and the effective concentration of acrolein was similar to that of spermine, whereas hydrogen peroxide was marginally toxic. Aminoguanidine, an inhibitor of amine oxidase, blocked the toxic effects of spermine on microglia. Spermine cytotoxicity was also prevented by antioxidant reagents; glutathione (reduced form), cysteine, and N-acetylcysteine. These results suggest that polyamine-induced apoptotic cell death of microglia is triggered by an oxidative stress with acrolein, which is produced by amine oxidase from polyamine. The different toxicities of polyamine between two glial cells may regulate the balance of glial activation in some pathological conditions of CNS.

Acrolein↗

PubMed2005

Importance of polyamines in cell cycle kinetics as studied in a transgenic system.

Polyamines are organic cations, which are considered essential for normal cell cycle progression. This view is based on results from numerous studies using a variety of enzyme inhibitors or polyamine analogues interfering with either the metabolism or the physiological functions of the polyamines. However, the presence of non-specific effects may be hard to rule out in such studies. In the present study, we have for the first time used a transgenic cell system to analyze the importance of polyamines in cell growth. We have earlier shown that expression of trypanosomal ODC in an ODC-deficient variant of CHO cells (C55.7) supported growth of these otherwise polyamine auxotrophic cells. However, one of the transgenic cell lines grew much slower than the others. As shown in the present study, the level of ODC activity was much lower in these cells, and that was reflected in a reduction of cellular polyamine levels. Analysis of cell cycle kinetics revealed that reduction of growth was correlated to prolongation of the G1, S, and G2+M phases in the cells. Providing exogenous putrescine to the cells resulted in a normalization of polyamine levels as well as cell cycle kinetics indicating a causal relationship.

Animals↗

PubMed1988

Value of urinary polyamines as noninvasive markers of cardiac allograft rejection in the dog.

A noninvasive marker of cardiac allograft rejection would be useful clinically. Lymphocyte proliferation and organ rejection may cause changes in urinary polyamine excretion. To test this hypothesis, cervical heterotopic heart transplantations were performed in a group of 6 nonimmunosuppressed dogs and in a group of 9 dogs treated with cyclosporine (N = 3) or cyclosporine and steroids (N = 6). A group (N = 3) having a sham operation was also studied. Serial biopsies of the transplanted hearts were performed. Urinary polyamine levels were measured daily by high-pressure liquid chromatography of urine specimens. Between 2 and 4 days after transplantation, the transplanted hearts of all animals without immunosuppression demonstrated histological rejection. An early increase in putrescine levels and in total urinary polyamine levels was observed in this group. In the treated groups, histological rejection appeared from the second to the eighth day after transplantation. Each episode of rejection occurred from 1 day to 4 days after a significant increase in urinary polyamine levels compared with the preoperative baseline level (p less than 0.01). In contrast, polyamine excretion in 3 dogs after sham operations remained unchanged. Thus, urinary excretion of polyamines increases before the appearance of histological rejection; this suggests that changes in urinary polyamine levels may be a useful marker of cardiac allograft rejection.

Animals↗

PubMed2002

Insufficiently charged isosteric analogue of spermine: interaction with polyamine uptake, and effect on Caco-2 cell growth.

We characterised a novel, charge-insufficient isosteric analogue of spermine, 11-[(amino)oxy]-4,9-diaza-1-aminoundecane (AOSPM). This analogue was synthesised by displacing aminopropyl group by aminooxyethyl group, the latter having pK(a) of about 5. Charge deficiency of the AOSPM molecule was fixed at a definite atom, while pK(a) of the rest nitrogen was similar to the parent polyamine. AOSPM competed with putrescine, spermidine and spermine for the uptake into the cell, and was accumulated in the cells in high amounts when exogenous polyamine synthesis was impaired. It was not recognised by the cells as growth-promoting polyamine, since it was unable to restore growth arrest due to polyamine deprivation. Like natural spermine, this polyamine analogue prevented oxidative DNA damage. AOSPM could be used not only as a tool to study polyamine homeostasis in the cell, but may have distinct applications either as radiation protector, a stable and non-toxic inhibitor of polyamine uptake or, as an appropriate vector, to enhance the uptake of impermeable compounds into the cell.

Analysis of Variance↗

PubMed1997

Postischemic, systemic administration of polyamine-modified superoxide dismutase reduces hippocampal CA1 neurodegeneration in rat global cerebral ischemia.

Antioxidant enzymes such as superoxide dismutase (SOD) have shown neuroprotective effects in animal models of cerebral ischemia, but only at very high doses. Modifications to increase the plasma half-life or blood-brain barrier (BBB) permeability of SOD have resulted in limited neuroprotective effects. No one has demonstrated neuroprotection with postischemic administration. The specific aim of the present study was to administer systemically a polyamine-modified SOD, having increased BBB permeability and preserved enzymatic activity, following global cerebral ischemia in rats and analyze the effects on the selective vulnerability of CA1 hippocampal neurons. Following 12 min of four-vessel occlusion, global cerebral ischemia, male Wistar rats were dosed (i.v.) with either saline, native SOD (5000 U/kg), polyamine-modified SOD (5000 U/kg), or enzymatically inactive, polyamine-modified SOD (2.1 mg/kg) twice daily for 3 days. Neuroprotective effects on hippocampal CA1 neurons were assessed using standard histological methods. Saline-treated animals had very few remaining CA1 neurons (1.44 +/- 0.60 neurons/reticle; x +/- S.E.M.) compared to sham rats (58.57 +/- 0.69). Native (10.38 +/- 2.96) or inactive, polyamine-modified SOD (7.32 +/- 2.68) did not show significant neuroprotective effects. Polyamine-modified SOD, however, resulted in the survival of significantly more CA1 neurons (24.61 +/- 5.90; P < 0.01). Postischemic, systemic administration of polyamine-modified SOD, having increased BBB permeability and preserved enzymatic activity, significantly reduced hippocampal CA1 neuron loss following global cerebral ischemia. Similar modification of other antioxidant enzymes and neurotrophic factors with polyamines may provide a useful technique for the systemic delivery of therapeutic proteins across the BBB for the treatment of stroke and other neurodegenerative disorders.

Animals↗

PubMed2001

Polyamines, NO and cGMP mediate stimulation of DNA synthesis by tumor necrosis factor and lipopolysaccharide in chick embryo cardiomyocytes.

OBJECTIVE: We have recently shown that tumor necrosis factor-alpha (TNFalpha) and lipopolysaccharide (LPS) stimulate DNA synthesis in chick embryo cardiomyocytes (CMs). The aim of the present research was to investigate the pathways involved in this mitogenic response. METHODS: CMs were isolated from 10-day-old chick embryos and grown to confluence. After 20 h of serum starvation the cells were treated with TNFalpha and LPS, and/or specific agonists and antagonists to manipulate the levels of polyamines, NO, cGMP and their biosynthetic enzymes ornithine decarboxylase (ODC), nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC). ODC, NOS, sGC activities and cGMP contents were determined by radiochemical procedures. DNA synthesis was determined by incorporation of [3H]-thymidine. RESULTS: Treatment of CMs with TNFalpha and LPS increased cell number and [3H]-thymidine incorporation. Addition of TNFalpha and LPS provoked an induction of ODC, with consequent polyamine accumulation, and a more delayed enhancement of NOS activity, which appeared to be independent of the activation of the ODC-polyamine system. TNFalpha and LPS treatment also enhanced cGMP level in CMs and both polyamine and NO biosyntheses appeared to be required. Experiments with specific inhibitors of ODC and NOS, as well as with inhibitors of sGC and cGMP-dependent protein kinase (PKG), showed that polyamine-, NO- and cGMP-dependent pathways are required for the mitogenic action of TNFalpha and LPS. Moreover, addition of exogenous polyamines to untreated cells raised the cGMP level in a NO-dependent fashion, and enhanced [3H]-thymidine incorporation. The latter effect was inhibited by sGC or PKG inhibitors. Treatment of quiescent cells with NO donors, 8-bromo-cGMP or YC-1, an sGC activator, also promoted DNA synthesis. Furthermore, putrescine and NO donor can additively activate sGC in cell-free extracts. CONCLUSION: TNFalpha and LPS stimulate DNA synthesis in chick embryo CMs and this effect is mediated by polyamines, NO and intracellular cGMP.

Alkaloids↗

PubMed1999

Polyamine deprivation alters formalin-induced hyperalgesia and decreases morphine efficacy.

Although the exact functions of polyamines in the nervous system remain still unclear, they are thought to have a physiological role in intracellular signal processing and neurotransmission. Polyamine deprivation which consists in the reduction of both the endogenous and exogenous sources of polyamines is a promising treatment for cancer. In a previous study we have shown that this treatment provokes an analgesic effect in rats submitted to brief phasic nociceptive tests. The present study examined the effect of polyamine deprivation on pain-related behaviors and spinal c-fos expression evoked in the formalin test presumed to better reflect clinical pain, using morphine as analgesia control. Polyamine deprivation per se altered the characteristic pain-related behaviors, reducing the interphase depression of pain, without inducing changes in the spinal Fos staining. In addition this treatment prevented the antinociceptive effect of morphine both on behavioral responses and on spinal c-fos expression. In polyamine-deprived rats, despite morphine injection, nociceptive scores remained dramatically high during the intermediate and the late phases of the response and the number of Fos immunoreactive neurons remained largely higher in deeper layers than in morphine control rats. Altogether these data support a modulatory role of polyamines both on the neuronal circuitry mediating sensory information, and on mechanisms underlying morphine analgesia.

Analgesics, Opioid↗

PubMed2002

Polyamine-mediated post-transcriptional regulation of COX-2.

Polyamines are involved in various cellular processes including embryonic development, cell growth and cell cycle regulation, apoptosis and carcinogenesis. Growing evidence suggests the importance of RNA processing and stability mediated by oncogenes and tumor suppressor genes in the development of cancer. Polyamines, which are found to be increased in neoplastic cells and tissues compared to normal, bind to RNA to influence its structure and function. Polyamines mediate RNA processing through the spermidine-regulated protein, eIF-5A. To further investigate how polyamines influence RNA expression, we characterized the polyamine-dependent RNA expression of a cancer-related gene, cyclooxygenase-2 (COX-2), which contains eIF-5A consensus binding elements. Depletion of polyamines by DL-alpha-difluoromethylornithine (DFMO) treatment caused an induction of COX-2 mRNA steady-state levels. Polyamines appear to regulate expression of COX-2 by a post-transcriptional mechanism.

3' Untranslated Regions↗

PubMed1997

Effects of chronically elevated growth hormone levels on polyamine metabolism in elderly transgenic mice.

The polyamines are ubiquitous, multifunctional aliphatic amines with roles in cell growth, proliferation, differentiation, and malignant development. After growth stimulation, rapid and transient changes occur in polyamine regulatory enzymes. In this respect, acute effects of growth hormone (GH) injection on polyamine metabolic enzymes have earlier been shown. The present investigation comprises studies of the effects on polyamine metabolism of constitutively elevated levels of circulating GH in elderly transgenic (tg+) mice, overexpressing bovine GH. Polyamine levels were found to be constitutively altered in the liver and kidney of tg+ mice. Less changes were found in the spleen and none in the brain. The cellular uptake of polyamines in the liver from tg+ mice showed an increase and considerable changes were observed in the activity of ornithine decarboxylase (ODC) in the liver and kidney and S-adenosylmethionine decarboxylase (AdoMetDC) in the liver. A conspicuous finding was the distribution pattern of ODC protein in the liver and both tg- and tg+ animals. The results show that the effects of chronically elevated GH levels are organ-dependent and complex, and differ from acute GH effects. Despite high ODC activity and polyamine levels in liver, these mice did not display any malignant transformation even at an advanced age, indicating that high ODC activity is not sufficient to induce tumorigenesis in vivo.

Adenosylmethionine Decarboxylase↗

PubMed2000

Interactions between agmatine and polyamine uptake pathways in rat pulmonary artery endothelial cells.

Agmatine, a product of arginine metabolism in vascular endothelial cells, is structurally similar to the natural polyamines, putrescine, spermidine and spermine. To test the hypothesis that agmatine and polyamines interacted at the level of the polyamine transporter, we determined if polyamines competed with agmatine for import and whether interventions modulating polyamine import exerted coordinate effects on agmatine uptake. Multiple lines of evidence were obtained to suggest that agmatine enters pulmonary artery endothelial cells (PAECs) via the polyamine transporter, though its intracellular disposition after uptake appears different from the natural polyamines.

Agmatine↗

PubMed2000

SOS induction of the recA gene by UV-, gamma-irradiation and mitomycin C is mediated by polyamines in Escherichia coli K-12.

Polyamines are involved in a wide range of cellular metabolism. In this study we investigated the effects of polyamines on the SOS induction of the recA gene by exposure to UV-, gamma-irradiation and mitomycin C employing polyamine-deficient mutant and wild type Escherichia. coli strains carrying recA'::'lacZ transcriptional fusion. In the polyamine-deficient mutant, the induction factor of the recA gene by UV-, gamma-irradiation and mitomycin C-treatment are about 3.0-, 2.5- and 4-fold lower, respectively, than those of the wild type. The exogenous addition of polyamines restored the reduced induction of the recA gene to the wild type level. Tri-amine spermidine effectively restored the recA induction to a level similar to the wild type, while being less restored by the di-amine putrescine. The restoration of recA induction by polyamines may be accomplished in a dose- and charge-dependent manner. Our results strongly suggest that polyamines may play an essential role as the SOS inducing mediator following exposure to damaging agents in E. coli and provide important information that tackles an interesting question in how cells respond to chemical and physical stresses.

DNA Repair↗

PubMedDate not supplied

Effect of polyamines on in vitro platelet aggregation and in vivo thrombus formation.

INTRODUCTION: Polyamines are polycations present in all living organisms and have been shown to play an important role in various physiological functions. Previous studies have shown that various amines including polyamines inhibited platelet activation, but there were no definitive studies testing their efficacy in an in vivo thrombosis model. We carried out detailed in vitro platelet aggregation studies using various concentrations of polyamines as well as agonists. METHODS: Platelet aggregation was measured by a turbidimetric method. Electric current induced in vivo thrombosis model is used for assessing antithrombotic effect. Incidence of bleeding was evaluated by template bleeding and incisional bleeding. RESULTS: Polyamines inhibited agonist-induced platelet aggregation in a dose-dependent manner. The inhibitory effect of polyamines is inversely proportional to the concentration of the agonist used. Among the polyamines, spermine is the potent inhibitor of platelet aggregation. A partially occlusive thrombus was generated by application of electric current in canine coronary artery. In control animals, the artery was completely occluded in 70 +/- 11 min after the current was discontinued. Blood flow remained patent for >240 min when 2 mg/kg spermine was given immediately after stopping the current. The antithrombotic effect of spermine was not associated with increased bleeding tendency. CONCLUSION: These results indicate that apart from inhibiting in vitro platelet aggregation polyamines can also inhibit in vivo thrombus formation. To our knowledge, this is the first study demonstrating this phenomenon.

Animals↗

PubMed2001

A mammalian sequence-dependent upstream open reading frame mediates polyamine-regulated translation in yeast.

In mammals, control of S-adenosylmethionine decarboxylase (AdoMetDC) translation is one component of a feedback network that regulates intracellular levels of the polyamines, spermidine, and spermine. AdoMetDC mRNA from mammals contains a highly conserved upstream open reading frame (uORF) within its leader sequence that confers polyamine-regulated suppression of translation on the associated downstream cistron. This regulation is mediated through an interaction that depends on the amino acid sequence of the uORF-encoded hexapeptide. It remains to be shown whether polyamines participate directly in this interaction or indirectly through a specialized signal transduction pathway. We show that Saccharomyces cerevisiae does not have a uORF associated with its AdoMetDC gene (SPE2) and that ribosome loading on the SPE2 mRNA is not positively influenced by polyamine depletion, as it is in mammalian cells. Nevertheless, the mammalian AdoMetDC uORF, when introduced into a polyamine auxotroph of yeast, conferred polyamine regulation of both translational efficiency and ribosome loading on the associated mRNA. This regulatory activity depended on the amino acid sequence encoded by the fourth and fifth codons of the uORF, as in mammalian cells. The fact that the regulatory properties of this mammalian translational control element are quite similar in both mammalian and yeast cells suggests that a specialized signal transduction pathway is not required. Rather, it seems likely that polyamines may be directly participating in an interaction between the uORF-encoded peptide and a constitutive component of the translation machinery, which leads to inhibition of ribosome activity.

Adenosylmethionine Decarboxylase↗

PubMed1993

Determination of total polyamines in tumor cells by high-performance capillary zone electrophoresis with indirect photometric detection.

Tumor cells contain much higher levels of common polyamines such as putrescine, spermidine, and spermine than normal cells. Our previous work demonstrated that high-performance capillary zone electrophoresis with indirect photometric detection was suitable for the determination of underivatized free polyamines in tumor cells. We now report improved sensitivity (7-fold), greater quantitative reproducibility, and quantitation of both bound and free, underivatized polyamines in PC 12 tumor cells. 1,7-Diaminoheptane was used as an internal standard for quantification. Femtomoles of three polyamines and simple cations such as K+ and Na+ were easily separated in less than 10 min. The quantitations for total spermidine and spermine (bound and free) were found to be 2-fold higher than the quantitation for free, unbound polyamines using our previous method. The signal response was linear over 2 orders of magnitude. The method described here provides a fast and simple technique for quantitation of bound, unbound, and total polyamines for use in the study of the biological role of polyamines.

Adrenal Gland Neoplasms↗

PubMed1981

Polyamine-activated protein kinase reaction from nuclei and nucleoli of Physarum polycephalum which phosphorylates a unique Mr 70 000 nonhistone protein.

Methods are described for the detection and purification of a protein kinase from nuclei and nucleoli of Physarum polycephalum which catalyzed transfer of phosphate from [gamma-32P]ATP to a unique nonhistone protein of Mr 70 000 in a reaction that was polyamine dependent. Enzymatic phosphorylation of the nonhistone protein by the purified protein kinase was stimulated greatly, at times more than 60-fold, by the polyamines spermidine and spermine. This unique polyamine-dependent reaction was localized on the rDNA minichromosome of the nucleolus. The polyamine-dependent protein kinase, which was first partially purified with the acidic nonhistone protein fraction from isolated nucleoli, was resolved from at least six other protein kinases by phosphocellulose chromatography into a catalytic component of Mr 26 000 and a complex comprised of the catalytic component associated with a phosphate acceptor protein of Mr 70 000. The complex also catalyzed polyamine-dependent phosphorylation of the endogenous Mr 70 000 component. The resolved catalytic component catalyzed polyamine-dependent phosphorylation of a dephosphorylated Mr 70 000 nonhistone protein that had been independently isolated from nucleoli and previously demonstrated to have properties concordant with a specific regulatory role in rRNA gene transcription [Keuhn, G. D., Affolter, H. U., Atmar, V. J., Seebeck, T., Gubler, U., & Braun, R. (1979) Proc. Natl. Acad. Sci. U.S.A. 76, 2541-2545]. These studies indicate one way that the polyamines may regulate rRNA gene transcription through the mediation of a highly specific nonhistone protein kinase.

Cell Nucleolus↗

PubMed2000

Self-assembly of an oligodeoxyribonucleotide harboring the estrogen response element in the presence of polyamines: ionic, structural, and DNA sequence specificity effects.

Estrogenic regulation of gene expression is mediated by the binding of the hormone to its specific receptor, estrogen receptor (ER), which undergoes structural and conformational alterations to recognize specific DNA sequences, estrogen response elements (ERE), in responsive genes to trigger a series of events culminating in the transcription of these genes. Polyamines are ubiquitous cellular cations that are important for cell growth and differentiation, and have been shown to participate in estrogenic regulation of gene expression. Polyamine-mediated DNA condensation/aggregation has been studied to understand the ionic and structural requirements for the compaction of DNA. DNA condensation/decondensation may also play a role in transcription and replication. We studied the aggregation of a 38-mer oligonucleotide duplex (ODN) in the presence of natural and synthetic polyamines under different ionic conditions (NaCl, KCl, and K glutamate). Our results showed that an ODN harboring the consensus ERE (ODN1) was 2-fold more susceptible to precipitation by spermine compared to ODN2 containing scrambled sequences, or a mutant ODN (ODN3). The nature of the monovalent cations (Na+ vs K+), and anions (Cl- vs glutamate) also played an important role in the efficacy of a polyamine to precipitate ODNs: potassium glutamate being the least effective in suppressing the ability of spermine to precipitate ODNs. The concentration of polyamines required for precipitating the ODNs increased with monovalent ion concentration in the buffer. With ODN1, a plot of log[spermine4+] at the 50% precipitation concentrations against log[Na+/K+] yielded a straight line, with a slope of 1.8 +/- 0.18, a value comparable to that predicted by the counterion condensation theory (1.85). We also observed significant structural specificity effects of spermine and its analogues [NH2(CH2)3NH(CH2)nNH(CH2)3NH2, where n = 2-9; n = 4 for spermine] on aggregating the ODN1. These results demonstrate DNA sequence and polyamine structural specificity effects on the aggregation of ODNs, and suggest that the gene regulatory function of ERE may be linked to its ability to undergo facile condensation/decondensation in the presence of biological cations, such as polyamines.

Base Sequence↗

PubMed1995

Synthesis of N,N'-substituted piperazine and homopiperazine derivatives with polyamine-like actions at N-methyl-D-aspartate receptors.

A series of N,N'-substituted piperazine and homopiperazine derivatives have been synthesized with the objective of producing compounds that interact with polyamine modulatory sites on N-methyl-D-aspartate (NMDA) receptors. These novel compounds exhibited polyamine-like actions, enhancing [3H]MK-801 binding to NMDA receptors in rat forebrain membranes. The potencies of N,N'-bis(2-aminoacetyl)homopiperazine (15), N,N'-bis(N-methyl-4-aminobutyl)-piperazine (7), and N,N'-bis(3-aminopropyl)homopiperazine (11) (EC50 18.0, 21.3, and 24.4 microM, respectively) to enhance [3H]MK-801 binding were comparable to that of spermine (EC50 5.2 microM). However, the efficacies of 15, 7, and 11 in this measure were lower (by approximately 40%, 32%, and 24%, respectively) than spermine, which may be indicative of partial agonist actions. Like spermine, the ability of these piperazine and homopiperazine derivatives to enhance [3H]MK-801 binding could be inhibited by both a competitive polyamine antagonist (arcaine) and a specific, noncompetitive polyamine antagonist (conantokin-G). However, unlike endogenous polyamines, high concentrations (up to 1 mM) of these novel polyamine-like compounds did not inhibit [3H]MK-801 binding. N,N'-Aminoalkylated and aminoacylated piperazine and homopiperazine derivatives may prove useful for studying polyamine recognition sites associated with NMDA receptors.

Animals↗