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Results for “Biogenic Polyamines”

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PubMed1999

Antitumor effects of bis(ethyl)polyamine analogs on mammary tumor development in FVB/NTgN (MMTVneu) transgenic mice.

We studied the therapeutic potential of two polyamine analogs on breast cancer using FVB/NTgN (MMTVneu), a transgenic mouse model with neu/erb-B2 oncogene overexpression. Treatment was initiated at 31 weeks of age with bis(ethyl)norspermine (BE333) and its higher homolog, BE3333 as i.p. injections once weekly. There was a 40% reduction in the average number of tumors per mouse in both treatment groups, by 10 weeks of treatment. BE3333-treated mice had 70-75% lower tumor volume than controls. Spermidine/spermine acetyl transferase activity was significantly higher in tumor tissues and kidneys of treated animals, whereas polyamine levels were lower than controls. Beneficial effects were also evident from the mortality rates in control and treatment groups. Our results suggest a potential use of selected bis(ethyl) polyamine analogs as antitumor agents in breast cancer.

Acetyltransferases↗
PubMed2002

Polylysine binding to unphosphorylated smooth muscle myosin enhances formation and stabilizes myosin filaments in vitro.

Previously, we demonstrated that positively charged polylysine, our model for biological polyamines, activates the Mg2+ ATPase activity of unphosphorylated smooth muscle myosin and shifts the myosin conformation from the folded 10S to linear 6S form. These effects of polylysine were reversed by the oppositely charged heparin (Szymanski et al. (1993) Am J Physiol 265, C379). In the present report, we provide further information on polylysine binding to smooth muscle myosin, and test the hypothesis that polylysine binding to unphosphorylated myosin involves filament formation. To relate the effects of polylysine on contractility in smooth muscle to physiologically relevant material, we investigated the ability of naturally occurring positively charged polyamines, histones, cadaverine, putrescine and spermidine to activate the Mg2+ ATPase activity of unphosphorylated smooth muscle myosin. Our data show that polylysine binding to individual unphosphorylated myosin molecules stimulates formation of myosin filaments. Polylysine also interacts with myosin filaments, causing enhancement of their size and the numbers, and this could be reversed by heparin. Polylysine binding to myosin filaments made them more resistant to disassembly by high salt concentrations (KCl) or ATP. Naturally occurring polyamines in millimolar concentrations activate the Mg2+ ATPase activity of unphosphorylated smooth muscle myosin. We suggest that the electrostatic interactions between naturally occurring positively charged polyamines and unphosphorylated smooth muscle myosin may play a role in stabilization of thick filament structurein situ.

Animals↗
PubMed2001

Role of polyamine metabolism in kainic acid excitotoxicity in organotypic hippocampal slice cultures.

Polyamines are ubiquitous cations that are essential for cell growth, regeneration and differentiation. Increases in polyamine metabolism have been implicated in several neuropathological conditions, including excitotoxicity. However, the precise role of polyamines in neuronal degeneration is still unclear. To investigate mechanisms by which polyamines could contribute to excitotoxic neuronal death, the present study examined the role of the polyamine interconversion pathway in kainic acid (KA) neurotoxicity using organotypic hippocampal slice cultures. Treatment of cultures with N1,N(2)-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72527), an irreversible inhibitor of polyamine oxidase, resulted in a partial but significant neuronal protection, especially in CA1 region. In addition, this pre-treatment also attenuated KA-induced increase in levels of lipid peroxidation, cytosolic cytochrome C release and glial cell activation. Furthermore, pre-treatment with a combination of cyclosporin A (an inhibitor of the mitochondrial permeability transition pore) and MDL 72527 resulted in an additive and almost total neuronal protection against KA toxicity, while the combination of MDL 72527 and EUK-134 (a synthetic catalase/superoxide dismutase mimetic) did not provide additive protection. These data strongly suggest that the polyamine interconversion pathway partially contributes to KA-induced neurodegeneration via the production of reactive oxygen species.

Animals↗
PubMed2006

Mammalian polyamine catabolism: a therapeutic target, a pathological problem, or both?

With the recent discovery of the polyamine catabolic enzyme spermine oxidase (SMO/PAOh1), the apparent complexity of the polyamine metabolic pathway has increased considerably. Alone or in combination with the two other known members of human polyamine catabolism, spermidine/spermine N(1)-acetyltransferase, and N(1)-acetylpolyamine oxidase (PAO), SMO/PAOh1 expression has the potential to alter polyamine homeostasis in response to normal cellular signals, drug treatment and environmental and/or cellular stressors. The activity of the oxidases producing toxic aldehydes and the reactive oxygen species (ROS) H(2)O(2), suggest a mechanism by which these oxidases can be exploited as an antineoplastic drug target. However, inappropriate activation of the pathways may also lead to pathological outcomes, including DNA damage that can lead to cellular transformation. The most recent data suggest that the two polyamine catabolic pathways exhibit distinct properties and understanding these properties should aid in their exploitation for therapeutic and/or chemopreventive strategies.

Acetyltransferases↗
PubMed1998

Facilitation of currents through rat Ca2+-permeable AMPA receptor channels by activity-dependent relief from polyamine block.

1. In outside-out patches excised from human embryonic kidney (HEK) 293 cells expressing Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptor (AMPAR) channels, currents activated by 1 ms glutamate pulses at negative membrane potentials facilitated during and following a repetitive (2 to 100 Hz) agonist application. The degree of facilitation depended on subunit type, membrane potential and stimulation frequency being antagonized by a slow recovery from desensitization. 2. Activity-dependent current facilitation occurred in Ca2+-permeable but not in Ca2+-impermeable AMPAR channels. Current facilitation, however, does not depend on Ca2+ flux. Rather it reflects a relief from the block of Ca2+-permeable AMPARs by intracellular polyamines since facilitation occurred only in the presence of polyamines and since facilitated currents had a nearly linear current-voltage relation (I-V). 3. Relief from polyamine block was use dependent and occurred mainly in open channels. The relief mechanism was determined primarily by membrane potential rather than by current flow. 4. In closed channels the degree of polyamine block was independent of membrane potential. The voltage dependence of the rate of relief from the block in open channels rather than the voltage dependence of the block underlies the inwardly rectifying shape of the I-V at negative potentials. 5. Currents through native Ca2+-permeable AMPAR channels in outside-out or nucleated patches from either hippocampal basket cells or a subtype of neocortical layer II nonpyramidal cells also showed facilitation. 6. It is concluded that a use-dependent relief from polyamine block during consecutive AMPAR channel openings underlies current facilitation. This polyamine-AMPAR interaction may represent a new activity-dependent postsynaptic mechanism for control of synaptic signalling.

Animals↗
PubMed1991

Effects of dexamethasone on the activity of histidine decarboxylase, ornithine decarboxylase, and dopa decarboxylase in rat oxyntic mucosa.

Since accelerated turnover of histamine in oxyntic mucosa may be an important factor in the pathogenesis of peptic ulcers, the effect of dexamethasone and other glucocorticoids on the activity of gastric histidine decarboxylase (HDC) was studied in the rat. The activity of HDC in rat oxyntic mucosa increased significantly after dexamethasone was injected s.c. to rats at doses larger than 0.4 mg/kg body weight. The maximum response of the HDC activity to dexamethasone (4 mg/kg) was observed 8 h after the treatment. The activity of ornithine decarboxylase (ODC) increased at 4 h, while that of DOPA decarboxylase showed no significant change throughout the 16-h period following a single injection of dexamethasone. The mucosal levels of histamine, putrescine, and spermidine rose significantly after the steroid treatment, while the spermine levels remained nearly constant. There was no sex difference in these responses to dexamethasone. Betamethasone showed nearly the same effects as dexamethasone on the decarboxylase activities and the mucosal levels of diamines. Serum gastrin levels showed no significant change for the first 4 h and then rose significantly 8 and 16 h after dexamethasone treatment. Pentagastrin (0.5 mg/kg) increased the HDC activity, while it showed no significant effect on either the mucosal ODC activity or levels of polyamines and histamine. These data suggest that dexamethasone influences the metabolism of histamine and polyamines in rat oxyntic mucosa both directly and via stimulation of gastrin release.

Animals↗
PubMed1998

Nitric oxide, free radicals and polyamines may have a role in the membrane pathology of schizophrenia.

Studies on skin fibroblasts in culture derived from schizophrenic and control subjects showed that polyamines are increased, nitrate levels are reduced and thiobarbituric acid reacting substances did not alter in cultured cells from schizophrenic patients compared to control subjects. Results seem to indicate some alteration in membrane functions in schizophrenia, which is susceptible to neuroleptic treatment. Significantly increased levels of polyamines in drug-treated schizophrenic cells indicates a possible role of polyamines in the activation of proposed hypofunctional NMDA subtype of glutamate receptor systems in schizophrenia.

Adolescent↗
PubMed1990

Polyamines in human gastrointestinal malignancies.

This study was designed to investigate the clinical relevance of polyamine determination in human tissue, serum, and urine as diagnostic markers in the diagnosis or postoperative control of patients with gastrointestinal cancer. Total, free, and acetylated polyamines were measured simultaneously in tissue, serum, and urine of patients with esophageal (n = 16), gastric (n = 40), pancreatic (n = 20) or colorectal (n = 50) carcinoma, in 40 patients with non-malignant gastrointestinal diseases, and 30 healthy volunteers. Though sensitivity of polyamines for gastrointestinal cancer proved to be high, non-malignant gastrointestinal diseases partly showed similar elevated polyamine concentrations in urine and serum which resulted in a low specificity of polyamines for gastrointestinal cancer. Therefore polyamines are not suitable as diagnostic markers in tumor screening. Furthermore, since polyamine concentrations in serum and urine normalized after curative operation while they were further increased and elevated in patients with proven relapse of the tumor or metastases, polyamines might be of clinical value in postoperative monitoring of therapeutical success or predicting relapse of the tumor.

Biogenic Polyamines↗
PubMedDate not supplied

[Polyamines in the gastrointestinal tract].

Polyamines are extremely important for cell growth, a fact that is reflected in the strict control of their synthesis and breakdown. In the small intestine, the polyamines play a fundamental role in all processes involving tissue regeneration, such as healing of stress-related ulcers, post-hepatectomy hepatic regeneration, adaptation syndrome after fasting and all processes with enterocyte hyperplasia or hypertrophy. In the gastrointestinal tract, there is a polyamine gradient in the villi-crypt cell axis and along the digestive tube, itself; the segments with greatest luminal content are the jejunum and the colon. Endogenous polyamine synthesis is stimulated by the diet and normal bacterial flora, which, in turn, regulate the amount and concentration of polyamines. Other hormonal and active peptide components (e.g. gastrin, epidermal growth factor, growth hormone) also have an influence on the pathway of polyamine synthesis. The interaction of these factors as related to the intestinal adaptive response is reviewed.

Animals↗
PubMed1997

Polyamine-dependent alterations in the structure of microfilaments, Golgi apparatus, endoplasmic reticulum, and proteoglycan synthesis in BHK cells.

The activity of ornithine decarboxylase, the key enzyme in the synthesis of polyamines, is essential for proliferation and differentiation of all living cells. Two inhibitors of ornithine decarboxylase, alpha-difluoromethylornithine (DFMO) and 1-aminooxy-3-aminopropane (APA), caused swelling of endoplasmic reticulum (ER) and medial and trans Golgi cisternae, and the disappearance of stress fibers, as visualized by staining with fluorescent concanavalin A (ConA), C6-NBD-ceramide or wheat germ agglutinin (WGA), and phalloidin, respectively. In contrast, the pattern of microtubules, stained with a beta-tubulin antibody, was not affected. Rough ER seemed to be especially affected in polyamine deprivation forming whorls and involutions, which were observed by transmission electron microscopy. Since ER and Golgi apparatus are vital parts of the glycosylation and secretory machinery of the cell, we tested the ability of these structurally altered cell organelles to synthesize proteoglycans using [3H]glucosamine and [35S]sulfate as precursors. The total incorporation rate into proteoglycans and hyaluronan was not reduced in polyamine-deprived cells, suggesting that the total glycosylation capacity of cells was not affected. However, the synthesis of a high molecular weight proteoglycan containing chondroitin and keratan sulfate was completely inhibited. The remodeling of cytoskeleton and rough endoplasmic reticulum in polyamine deprivation may perturb the synthesis and secretion of the components of membrane skeleton and of the extracellular matrix, e.g., proteoglycans. Rough ER and cytoskeleton may be the targets where polyamines affect cell proliferation and differentiation.

Actin Cytoskeleton↗
PubMed1998

Two active copies of the X-linked gene spermidine/spermine N1-acetyltransferase (SSAT) in a female lung cancer cell line are associated with an increase in sensitivity to an antitumor polyamine analogue.

The expression of the polyamine catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT), has been associated with tumor sensitivity to antitumor polyamine analogues. In the sensitive cell types the level of SSAT is greatly induced by these agents. Although SSAT expression is regulated at many levels, the initial regulation of this X-linked gene occurs at the level of transcription. Because most previous work in human cell lines has been performed in cells of male origin and because the SSAT gene is located near the pseudoautosomal region of the X chromosome, we investigated the possibility that both copies of SSAT could be expressed in normal and tumor cells in women. DNA methyl-sensitive restriction enzyme analysis of DNA from normal peripheral lymphocytes suggested that like most X-linked genes, only one copy of SSAT is actively transcribed. However, in an examination of four representative human lung tumor cell lines derived from women, two were found to have a methylation pattern identical to male-derived cells, suggesting a reactivation of the normally inactive allele or loss of the inactive allele. Microsatellite repeat polymorphism analysis indicated that one of the lines, a female carcinoid line, NCI H727, had reactivated the previously inactive copy, thus providing H727 with two active alleles, whereas a small cell lung cancer line, H889, appears to have lost the inactive allele. Most importantly, the H727 line expressed high amounts of SSAT mRNA and protein in response to treatment with the polyamine analogue, N1,N12-bis(ethyl)spermine, a compound known to increase SSAT transcription in sensitive cell types. H727 was also the only female line that responded to treatment in a cytotoxic manner. These data suggest that both copies of the SSAT allele may be expressed and that the inappropriate expression of the second copy can lead to an increase in tumor sensitivity to polyamine analogues that induce SSAT.

Acetyltransferases↗
PubMed1989

Microbial flora in the gastrointestinal tract abolishes cytostatic effects of alpha-difluoromethylornithine in vivo.

Although treatment with the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) leads to depletion of intracellular polyamines and to related growth inhibition in vitro, its cytostatic effects in vivo are disappointing. This may be due to abolition of DFMO-induced growth inhibition by polyamines released during normal body cell turnover, to dietary polyamines, or to putrescine synthesized by the microbial flora in the GI tract. We studied selectively (aerobic) and totally (aerobic + anaerobic) GI tract-decontaminated LI210-bearing mice fed with 3 types of diet differing in their polyamine and carbohydrate residue contents and treated with combinations of intraperitoneal DFMO and oral deuterium-labelled putrescine. Our data show that, irrespective of diet type, total decontamination markedly potentiates the moderate tumor growth inhibition that is caused by DFMO alone. During total decontamination, growth-inhibited L1210 cells accumulate in the G0/G1 phase of the cell cycle. Although orally administered deuterium-labelled putrescine gave rise to deuterium labelling of L1210 putrescine, spermidine and spermine, the polyamine levels in our diets played only a minor role.

Animals↗
PubMed2003

The putrescine analogue 1-aminooxy-3-aminopropane perturbs polyamine metabolism in the phytopathogenic fungus Sclerotinia sclerotiorum.

The effects of the putrescine analogue 1-aminooxy-3-aminopropane on fungal polyamine metabolism were evaluated using Sclerotinia sclerotiorum as an experimental model. The compound inhibited ornithine decarboxylase, spermidine synthase, and S -adenosyl-methionine decarboxylase in mycelial extracts. Addition of 1-aminooxy-3-aminopropane at 1 mM to the culture medium did not reduce mycelial growth and caused a 29% decrease in free spermidine and a two-fold increase in free spermine. When added 4.5 h before the determination of ornithine decarboxylase, 1-aminooxy-3-aminopropane reduced in vivo activity of this enzyme by 40-50%. When added 48 h before the determination, 1-aminooxy-3-aminopropane at 0.01 and 0.1 mM caused a slight increase of in vivo ornithine decarboxylase activity, while it had no effect at 1 mM. Comparison of the action of 1-aminooxy-3-aminopropane with that of other inhibitors of polyamine biosynthesis suggested that its effects on in vivo ornithine decarboxylase activity resulted from a balance between direct inhibition of enzyme activity and indirect stimulation of enzyme synthesis and/or activity mediated by the decrease in spermidine levels, which in turn was due to inhibition of spermidine synthase and S -adenosyl-methionine decarboxylase. The potential of 1-aminooxy-3-aminopropane as a tool for studies on fungal polyamine metabolism and for the control of plant diseases of fungal origin is discussed.

Adenosylmethionine Decarboxylase↗
PubMed1993

The interaction of 2,4-dichlorophenoxyacetic acid, ribosomes and polyamines in Azospirillum brasilense.

2,4-Dichlorophenoxyacetic acid (2,4-D) is an herbicide used extensively in agriculture. We had previously determined that 1 mM 2,4-D could inhibit cell growth, DNA and protein synthesis of Azospirillum brasilense. The present work was designed to determine if these alterations are a consequence of 2,4-D action on polyamine biosynthesis and if the protein synthesis inhibition is a result of ribosomal impairment. In this paper we demonstrate that 2,4-D alters the metabolism of polyamines and, thus, affects protein synthesis at the ribosomal level.

2,4-Dichlorophenoxyacetic Acid↗
PubMedDate not supplied

Age-related changes in polyamine biosynthesis after fasting and refeeding.

The effect of aging on ornithine decarboxylase (ODC) activity and polyamine biosynthesis in the proximal small intestine was studied in two groups of male Fisher 344 rats (young [4-month old] and aged [26- to 27-month old]) using a fasting and refeeding model. In control (nonfasted) rats, levels of polyamines (putrescine, spermidine and spermine) and ODC activity were significantly higher in aged compared with young rats. In aged rats, fasting significantly reduced the levels of putrescine by 41%, spermidine by 23%, and spermine by 11%; however, fasting had no effect on polyamine levels in young rats. ODC activity was decreased 75% in young and 50% in aged rats after fasting compared with the respective age-matched controls. Conversely, 2 h after reinstituting a chow diet increased ODC activity by 17-fold in young rats but only 8-fold in aged rats. Putrescine levels were also increased in both age groups after refeeding; however, similar to ODC activity, these increases were much less in aged rats. In addition, spermidine and spermine levels remained significantly depressed in the aged groups even after 24 h of refeeding. These findings suggest that the normal rigid control of gut polyamine biosynthesis and proliferation noted in young rats is markedly altered with aging.

Aging↗
PubMed2000

Determination of hair polyamines as N-ethoxycarbonyl-N-pentafluoropropionyl derivatives by gas chromatography-mass spectrometry.

An efficient method is described for the simultaneous determination of hair polyamines, such as 1,3-diaminopropane, putrescine, cadaverine, spermidine and spermine, by gas chromatography-mass spectrometry (GC-MS) with the selected ion-monitoring (SIM) mode. The method is based on the extractive two-phase ethoxycarbonyl (EOC) reaction of amino functions in aqueous solutions combined with subsequent pentafluoropropionyl (PFP) derivatization of the remaining active hydrogen atoms for the direct analysis by GC-SIM-MS. The detection limits for SIM of the polyamines as N-EOC-N-PFP derivatives ranged from 1 to 10 ng/g hair, while their recovery rates varied in the range of 76.42-93.38%. This method demonstrated a good overall accuracy (% bias) and precision (% C.V.) as 3.32-11.05% and 5.88-14.71%, respectively. When applied to 0.6 M HCl extracts of hair samples from 11 healthy men and 19 healthy women, all five polyamines were positively detected at the concentrations of 8.82-871.87 ng/g. Both in median and mean concentrations, the most abundant hair polyamine was spermidine, followed by spermine, putrescine, 1,3-diaminopropane and cadaverine in the male group, while the order of 1,3-diaminopropane and cadaverine was reversed in the female group. The levels of polyamines, except for cadaverine, in hair specimens studied were found to be higher in men than in women.

Adult↗
PubMed1998

Estrogens and polyamines in breast cancer: their profiles and values in disease staging.

The urinary concentrations of 16 estrogens and 11 polyamines were quantitatively determined by gas chromatography-mass spectrometry and gas chromatography with nitrogen-phosphorus detection. Samples from patients with stages I-IV of breast cancer (35 cases, aged 27-65 years) as well as from age-matched normal female subjects (25 cases, aged 22-61 years) were tested. Also, the ratios of precursor to product metabolite including 16alpha-OH E1 to 2-OH E1, which are linked to estrogen and polyamine biosynthetic pathways, were determined to explore enzyme involvement in breast cancer and to evaluate the potential usefulness of these ratios and concentrations as disease staging markers. It was confirmed that major estrogens and 16a-OH E1 were positively associated with breast cancer and catechol estrogens including 2-OH E1 were inversely associated with breast cancer. The ratios of N1-acSp/Spd and 16alpha-OH E1/2-OH E1 might be a useful dual marker for staging of breast cancer. From the variation of the relative ratios of polyamines, it is suggested that alteration in polyamine oxidase (PAO) activity may play an important role in the development of breast cancer.

Adult↗
PubMed2003

Translational regulation of the plant S-adenosylmethionine decarboxylase.

It is becoming apparent that control of protein synthesis by metabolites is more common than previously thought. Much of that control is exerted at the level of initiation of mRNA translation, orchestrated by upstream open reading frames (uORFs) and RNA secondary structure. S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in polyamine biosynthesis and both mammalian and plant AdoMetDCs are translationally regulated by uORFs in response to polyamine levels by distinct mechanisms.

Adenosylmethionine Decarboxylase↗