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PubMed1991

Correlations between polyamine analogue-induced increases in spermidine/spermine N1-acetyltransferase activity, polyamine pool depletion, and growth inhibition in human melanoma cell lines.

The polyamine analogue, N1,N12-bis(ethyl(-spermine (BESPM), is known to suppress ornithine and S-adenosylmethionine decarboxylase levels, deplete intracellular polyamine pools, and inhibit cell growth. Among human melanoma cell lines, MALME-3 cells were found to be typically sensitive to the antiproliferative activity of the BESPM, whereas LOX cells were atypically insensitive to the analogue. A comparison of polyamine-related parameters revealed that the most differentially altered activity between the 2 BESPM-treated cell lines was that of spermidine/spermine N1-acetyltransferase (SSAT), which increased from 50 pmol/min/mg to greater than 10,000 pmol/min/mg in MALME-3 cells and from 16 pmol/min/mg to only 120 pmol/min/mg in LOX cells over 48 h. The basis for the large difference seems to be related to increased enzyme synthesis in both cell lines coupled with differences in prolongation of SSAT half-life (greater than 12 h in MALME-3 cells versus 1.6 h in LOX cells) after BESPM treatment. In MALME-3 cells, SSAT accumulation was found to be differentially modulated by the BESPM homologues, N1,N11-bis-(ethyl)norspermine and N1,N14-bis-(ethyl)homospermine, which were 5-fold more and 9-fold less effective, respectively, than BESPM in increasing SSAT but similar in analogue uptake and effects on polyamine biosynthesis and cell growth inhibition. Treatment of MALME-3 cells with BESPM resulted in an accumulation of N-acetylspermidine in cells and the enhanced excretion of putrescine, spermidine, and N-acetylspermidine into the medium. The relationship between SSAT induction and growth sensitivity was deduced to be a possible function of increased excretion of acetylated polyamines leading to enhanced polyamine pool depletion. The data suggest that, in cell types in which it occurs, unusually high increases in SSAT activity may serve as a determinant of growth sensitivity to bis-ethyl spermine analogues or, alternatively, as a target for appropriately designed chemotherapeutic strategies.

Acetyltransferases↗
PubMed1998

Nitric oxide synthase inhibitors attenuate phencyclidine-induced disruption of prepulse inhibition.

Glutamate stimulation of N-methyl-D-aspartate (NMDA) receptors results in release of nitric oxide which may mediate the effects of NMDA receptor stimulation and/or may result in feedback inhibition of the presynaptic neuron. Results of a previous study showed that nitric oxide synthase (NOS) inhibitors blocked dizocilpine-induced behavior in mice. In the present study, NOS inhibitors were tested in combination with phencyclidine (PCP), a drug which typically dose-dependently disrupts prepulse inhibition of the acoustic startle response in rats. Alone, NOS inhibitors and promoters do not affect prepulse inhibition; however, when tested in combination with PCP, the NOS inhibitors, L-NOARG, 7-nitroindazole and arcaine--but not the NR2B-selective polyamine site NMDA antagonist, eliprodil--attenuated PCP-induced disruption of prepulse inhibition of the acoustic startle response. These effects are similar to those produced by many atypical antipsychotics and suggests that this class of drugs should be investigated further for their potential utility as antipsychotics and as treatments for PCP abuse.

Acoustic Stimulation↗
PubMed2006

Reproducibility and expression of skin biomarkers in sun-damaged skin and actinic keratoses.

OBJECTIVES: To explore p53 and proliferating cell nuclear antigen (PCNA) expression and polyamine content as biomarkers in skin cancer chemoprevention trials, we evaluated their expression in early stages of UV-induced squamous cell tumorigenesis. METHODS: Biopsies were collected from three groups: 78 subjects with sun damage on forearms, 33 with actinic keratosis (AK) on forearms, and 32 with previous squamous cell carcinoma. Participants with sun damage were randomized to sunscreen or no sunscreen. RESULTS: We found significant differences in p53 and polyamines in forearms from the sun-damaged group (11.5 +/- 1.2% for p53, 65.5 +/- 1.9 nmol/g for putrescine, and 187.7 +/- 3.3 nmol/g for spermidine) compared with the group with sun damage plus AK (20.9 +/- 2.3% for p53, P = 0.0001; 81.7 +/- 3.9 nmol/g for putrescine, P = 0.0001; 209.4 +/- 8.2 nmol/g for spermidine, P < 0.06). PCNA was not different. When lesion histology was considered, there was a stepwise significant increase in p53 in biopsies without characteristics of AK compared with early AK (P = 0.02) and AK (P = 0.0006) and a similar pattern for PCNA with the only significant difference between early AK and AK. There was a stepwise increase in putrescine and spermidine in normal, sun-damaged forearm, forearm from subjects with AK, and the AK lesion itself (P < 0.0001). No significant differences in p53 or polyamines were seen in 3-month biopsies or, as a result of sunscreen use, although PCNA in the sun-damaged group not using sunscreen decreased significantly. CONCLUSIONS: p53 expression and polyamines in skin were elevated in early stages of skin tumorigenesis and were not affected by sunscreen, adding validity to their use as biomarkers in skin cancer chemoprevention trials.

Adult↗
PubMed1992

Role of ornithine decarboxylase suppression and polyamine depletion in the antiproliferative activity of polyamine analogs.

Two transfected cell lines, one carrying a mammalian ornithine decarboxylase (ODC) that is suppressed by polyamines and one carrying a trypanosomal ODC that is not, were used to ask whether ODC suppression is necessary for the antiproliferative activities of two polyamine analogs, N1,N8-bis(ethyl)spermidine (BES) and N1,N14-bis(ethyl)homospermine (BE444). Both analogs accumulated within cells and suppressed S-adenosylmethionine decarboxylase, as well as polyamine-sensitive mouse ODC activity. Neither drug was able to suppress the activity of the polyamine-refractory trypanosome ODC. But, whereas BE444 was able to inhibit growth of both cell lines, BES could inhibit only growth of cells carrying the polyamine-sensitive ODC, under conditions that cause prolonged depletion of endogenous polyamines. We conclude from these studies that the antiproliferative activity of BES, a less potent drug, requires the suppression of ODC. The efficacy of BE444 is enhanced by its ability to suppress ODC. However, it can function without ODC suppression, whereas BES cannot.

Adenosylmethionine Decarboxylase↗
PubMed1992

The additive effect of alpha-difluoromethylornithine (DFMO) and radiation therapy on a rat glioma model.

The effects of alpha-difluoromethylornithine (DFMO), radiation and the therapy of their combination were investigated in rats bearing G-XII glioma. DFMO treatment as well as radiation therapy prolonged the survival period when compared to the results in non-treated control rats. The combination therapy showed a greater effect on the survival rate than the single therapies, the effect being additive. The concentration of putrescine, spermidine, and N1-acetylspermidine in tumor tissue was lowered by DFMO, while that of spermine was slightly elevated. Radiation decreased the concentration of all the polyamines, putrescine, spermidine, spermine and N1-acetylspermidine. The concomitant treatment with DFMO and radiation further decreased the concentrations of putrescine and N1-acetylspermidine in tumor tissues. The survival period of glioma-bearing rats is inversely correlated with the tissue levels of putrescine plus N1-acetylspermidine.

Animals↗
PubMed2005

Regional and temporal alterations of ODC/polyamine system during ALS-like neurodegenerative motor syndrome in G93A transgenic mice.

Natural polyamines (putrescine, spermidine and spermine) are ubiquitous molecules known to regulate a number of physiological processes and suspected to play a role also in various pathological conditions. Changes in polyamine levels and in their biosynthetic enzymes have been described for some neurodegenerative diseases but the available data are incomplete and somewhat contradictory. We report here alterations of the key enzyme of the polyamine pathway, ornithine decarboxylase (ODC) catalytic activity and polyamine levels in different CNS areas from SOD1 G39A transgenic mice, an animal model for amyotrophic lateral sclerosis (ALS). ODC catalytic activity, was found significantly increased both in the cervical and lumbar spinal cord and, to a lesser extent in the brain stem of transgenic mice at a symptomatic stage of the disease (125-day-old mice), while no differences were present at a pre-symptomatic stage (55-day-old mice). In parallel with the increase of ODC activity putrescine levels were several times increased in both cervical and lumbar spinal cord and in the brain stem of 125-day-old SOD1 G39A mice. Higher order polyamines were not increased except for a significant increase of spermidine in the cervical spinal cord. The present data demonstrate considerable alterations of the ODC/polyamine system in a reliable animal model of ASL, consistent with their role in neurodegeneration and in particular in motor neuron diseases.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Distribution of two triamines, spermidine and homospermidine, and an aromatic amine, 2-phenylethylamine, within the phylum Bacteroidetes.

Cellular polyamines of the newly additional 19 species belonging to the class Bacteroides of the phylum Bacteroidetes were analyzed by HPLC to display polyamine distribution as a chemotaxonomic marker within the total 41 species. Three profiles, the presence of spermidine, the presence of homospermidine and the absence of both triamines, corresponded to their phylogenetical positions within the four families of the class. The occurrence of an aromatic amine, 2-phenylethylamine, extracted into cellular polyamine fraction, was also determined within the 121 species distributed within the phylum. This aromatic amine was found in Cellulophaga lytica, Cytophaga latercula, Tenacibaculum amylolyticum, Tenacibaculum martimum, Tenacibaculum mesophilum and Psychroflexus torquis belonging to the family Flavobacteriaceae of the class Flavobacteria, and Flexibacter flexilis and Microscilla marina belonging to the family Flexibacteraceae of the class Sphingobacteria.

Bacteroidetes↗
PubMed1990

Effect of dietary putrescine on whole body growth and polyamine metabolism.

Putrescine (1,4-diaminobutane) is the simplest of the mammalian polyamines. These are small, positively charged molecules which are essential for cell growth and are thought to play a role in regulation of anabolic events such as synthesis of DNA, RNA, and protein. Recent reports have indicated the potential for dietary precursor amino acids of putrescine to alter tissue putrescine concentrations. The current study was conducted to determine the physiologic significance of these effects by feeding up to flooding doses of putrescine to determine any influence on whole body growth and polyamine metabolism. A total of 96 chicks were fed purified crystalline amino acid diets containing 0.0, 0.2, 0.4, 0.6, 0.8, or 1.0% purified putrescine (four birds per pen, four pens per diet) for 14 days. The feeding of 0.2% putrescine increased growth rate beyond that of controls while further supplements reduced growth and were toxic when 0.8 and 1.0% putrescine were fed. Hepatic and muscle concentrations of ornithine increased with dietary putrescine while the effect in kidney was much less. Putrescine concentrations in liver, kidney, and muscle rose when 0.4% putrescine or more was fed. This effect was particularly obvious in muscle in which there were also increases in the concentrations of spermidine and spermine. In a subsequent similar experiment, putrescine was fed at 0.0, 0.1, 0.2, 0.3, 0.4, or 0.5% to determine the effect on the activities of the key enzymes regulating polyamine synthesis. The feeding of putrescine at even 0.1% caused a rapid reduction in hepatic ornithine decarboxylase activity while S-adenosylmethionine decarboxylase and arginase activities were not influenced by diet. It was concluded that excess tissue putrescine can be toxic to whole organisms but small, orally administered doses of this metabolite can promote growth.

Amino Acids↗
PubMed1991

The effects of N-methyl-D-aspartate and kainate lesions of the rat striatum on striatal ornithine decarboxylase activity and polyamine levels.

The intrastriatal injection of N-methyl-D-aspartate (NMDA) (250 nmol) produced a delayed and marked increase in striatal ornithine decarboxylase (ODC) activity and putrescine levels which peaked 6-15 h following the injection of NMDA. Striatal ODC activity subsequently returned to normal values while putrescine levels remained significantly elevated for up to 4 days following the lesion. NMDA produced an early and progressive decline in striatal spermine and spermidine levels, preceding the increase in ODC activity, with a maximum effect 2 h following injection. Spermidine levels returned to normal 6 h post-NMDA infusion, and subsequently increased to above normal levels 36 h and 4 days after the infusion of NMDA. This late increase in striatal spermidine levels paralleled an increase in the binding of the glial cell/macrophage marker [3H]PK 11195. Spermine levels tended to return to normal values 6 h after the injection of NMDA but may be further depressed at later intervals (15 h to 4 days). The intrastriatal injection of saline also resulted in a delayed increase in striatal ODC activity and putrescine levels, but these changes were minor compared to those produced by NMDA. Intrastriatal saline injection provoked no consistent change in striatal spermine or spermidine levels. The changes in polyamine metabolism produced by the intrastriatal injection of kainic acid (4 nmol) were only analysed at 6 and 15 h following injection but were qualitatively similar to those produced by NMDA although perhaps following a slightly more delayed time-course.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Polyamine metabolism of enterocyte-like Caco-2 cells after exposure to Phaseolus vulgaris lectin.

The effect of Phaseolus vulgaris isolectin E4 on polyamine concentrations and ornithine decarboxylase activity of proliferating and differentiating Caco-2 cells was investigated. Values of putrescine, spermidine, and spermine in control cells were highest during the early phase of proliferative cell growth and lowest in the stationary phase. Phytohaemagglutinin E4 significantly increased cellular polyamine values during the late proliferative phase of cell growth. Ornithine decarboxylase activity was high during intensive proliferation and growth, but was lower when proliferation slowed down or ceased. Exposure of Caco-2 cells in the early proliferative phase of cell growth to increasing concentrations of the potent intestinal growth factor phytohaemagglutinin E4 greatly stimulated enzyme activity. In contrast, the activity of ornithine decarboxylase was not stimulated in Caco-2 cells of the late proliferative phase nor was there any increase in the enzyme activity in differentiating and fully differentiated cells of the stationary phase. Accordingly, when proliferating Caco-2 cells possessed the highest ornithine decarboxylase activity, the polyamine values were also at their highest. During differentiation, as the ornithine decarboxylase activity fell close to zero, polyamine values also decreased. In the early proliferative phase of cell growth ornithine decarboxylase activity coincided with DNA synthesis in cells exposed to Phaseolus vulgaris isolectin E4. These findings with Caco-2 cells were similar to those found in brush border cells of the rat small intestine.

Biogenic Polyamines↗
PubMed2001

Polyamine depletion in human melanoma cells leads to G1 arrest associated with induction of p21WAF1/CIP1/SDI1, changes in the expression of p21-regulated genes, and a senescence-like phenotype.

The cell cycle regulatory events that interface with polyamine requirements for cell growth have not yet been clearly identified. Here we use specific inhibitors of polyamine biosynthetic enzymes to investigate the effect of polyamine pool depletion on cell cycle regulation. Treatment of MALME-3M cells with either the ornithine decarboxylase inhibitor alpha-difluoromethylornithine or the S-adenosylmethionine decarboxylase inhibitor MDL-73811 lowered specific polyamine pools and slowed cell growth but did not induce cell cycle arrest. By contrast, treatment with the combination of inhibitors halted cell growth and caused a distinct G1 arrest. The latter was associated with marked reduction of all three polyamine pools, a strong increase in p21(WAF1/CIP1/SDI1) (p21), and hypophosphorylation of retinoblastoma protein. All effects were fully prevented by exogenous polyamines. p21 induction preceded p53 stabilization in MALME-3M cells and also occurred in a polyamine-depleted, p53-nonfunctional melanoma cell line, indicating that p21 is induced at least in part through p53-independent mechanisms. Conditional overexpression of p21 in a fibrosarcoma cell line was shown previously to inhibit the expression of multiple proliferation-associated genes and to induce the expression of genes associated with various aspects of cell senescence and organism aging. Polyamine depletion in MALME-3M cells was associated with inhibition of seven of seven tested p21-inhibited genes and with induction of 13 of 14 tested p21-induced genes. p21 expression is also known to induce a senescence-like phenotype, and phenotypic features of senescence were observed in polyamine-depleted MALME-3M cells. Cells increased in size, appeared more granular, and expressed senescence-associated beta-galactosidase. Cells released from the polyamine inhibition lost the ability to form colonies, failed to replicate their DNA, and approximately 25% became bi- or multinucleated. These events parallel the outcome of prolonged p21 induction in fibrosarcoma cells. The results of this study indicate that polyamine pool depletion achieved by specific biosynthetic enzyme inhibitors causes p21-mediated G1 cell cycle arrest followed by p21-mediated changes in gene expression, development of a senescence-like phenotype, and loss of cellular proliferative capacity.

Adenosylmethionine Decarboxylase↗
PubMedDate not supplied

[Polyamines in the hypothalamus and hippocampus after the changes in corticosteroid levels in rats].

Adrenalectomy as well as single or multiple hydrocortisone and ACTH administration have been studied for their effect on putrescine, spermidine and spermine contents, ornithine decarboxylase and S-adenosyl-+methionine decarboxylase activities in the rat hypothalamic and hippocampal tissues and fraction of nervous endings. The data obtained prove complicated character of changes in polyamine metabolism in the studied structures when glucocorticoid level is disturbed. Hormone action is characterized by regional and intracellular specificity and depends upon the ratio of administration and the initial hormonal background of the organism. The significance of these changes for feedback regulation of ACTH secretion and metabolism of GABA is discussed.

Adrenalectomy↗
PubMed1991

Amelioration of thrombocytopenia with concomitant ornithine in sarcoma-bearing rats receiving high dose difluoromethylornithine.

The dose limiting toxicity of difluoromethylornithine (DFMO), when administered by continuous infusion, is thrombocytopenia. DFMO-induced antitumor activity and thrombocytopenia were time- and dose-dependent up to 1700 mg/kg/d when administered continuously for 12 days. Concomitant ornithine administration (at selected molar ratios to DFMO) ameliorated thrombocytopenia induced by DFMO at a dose of 2000 mg/kg/day without adversely affecting its antitumor activity. The purpose of this study was to determine if ornithine could ameliorate the thrombocytopenia of higher DFMO doses and increase the efficacy of DFMO. Fischer 344 male rats with a transplantable sarcoma in the right flank were given 2000 and 3500 mg/kg/d DFMO alone or with ornithine at a molar ratio of 0.4 for 8 days by continuous infusion. Concomitant ornithine infusion overcame the thrombocytopenia that was induced by either dose of DFMO without reducing the antitumor activity against the sarcoma. The antitumor activity, tumor polyamine levels, and tumor S-adenosylmethionine decarboxylase activity did not consistently change with increasing doses of DFMO or with the addition of ornithine to the infusion regimen. These results demonstrate that the thrombocytopenia induced by doses of DFMO greater than 2000 mg/kg/d can be ameliorated without compromising the antitumor activity.

Animals↗
PubMed1995

Cationic porphyrin derivatives as inhibitors of polyamine catabolism.

The effects of six cationic porphyrins on several enzymes involved in polyamine biosynthesis and catabolism have been examined. Both spermidine and spermine synthase were unaffected by the porphyrins at up to 2 mM. By contrast, ornithine and S-adenosylmethionine decarboxylase were inhibited by the nickel and cobalt derivatives of meso-tetrakis(N-methyl-4-pyridiniumyl)porphyrin (T4MPyP) with IC50 values in the 10-100 microM region. Spermidine/spermine N1-acetyltransferase (SSAT) and polyamine oxidase (PAO) were highly sensitive to the six meso-substituted cationic porphyrins tested, with Ki values as low as 6 nM for SSAT and 85 nM for PAO. These inhibitors may prove useful in defining the structural features of the active site of these enzymes.

Acetyltransferases↗
PubMed2005

Pharmacological aspects of cytotoxic polyamine analogs and derivatives for cancer therapy.

During the past 20 years, numerous derivatives and analogues of spermidine (Spd) and spermine (Spm) were synthesized with the aim to generate a new type of anticancer drug. The common denominator of most cytotoxic polyamine analogues is their lipophilicity, which is superior to that of the parent amines. The natural polyamines bind to polyanions and to proteins with anionic binding sites. Their hydrophilicity/hydrophobicity is balanced, allowing them to perform physiological functions by interacting with some of these anionic structures, without impairing the functionality of others. Because the attachment of lipophilic substituents to the polyamine backbone increases the binding energy, lipophilic polyamine derivatives affect secondary and tertiary structures of a larger number of macromolecules than do their natural counterparts. In addition, lipophilicity improves the blood-brain barrier transport and thus enhances CNS toxicity. Close structural analogues of spermidine and spermine mimic the natural polyamines in regulatory functions. The cytotoxic mechanisms of analogues with a less close structural resemblance to spermidine or spermine have not been completely clarified. The displacement of spermidine from functional binding sites and the consequent prevention of its physiological roles is a likely mechanism, but many others may play a role as well. Up to now, polyamine analogues were conceived without specific growth-related targets in mind. To develop therapeutically useful drugs, it will be imperative to identify specific targets and to design compounds that interact selectively with the target molecules. It will also be necessary to include, at an early state of the work, pharmacological and toxicological considerations, to avoid unproductive directions.

Animals↗
PubMed2000

Alterations on polyamine content and glutathione metabolism induced by different concentrations of paraquat in CHO-K1 cells.

The effect of herbicide paraquat has been assessed on CHO-K1 cultures at different concentrations. Glutathione peroxidase, reductase and S-transferase, as well as total and oxidized glutathione, were evaluated along the standard growth curve of the cultures. Paraquat was then administered during mid-log phase at concentrations that produced a calculated lethality of 6.25%, 12.5% and 25%, using the lysosomal dye assay, neutral red. After 24hr of incubation with paraquat, glutathione peroxidase suffered a large dose-response increase, unlike glutathione reductase and S-transferase, the activities of which were lower than untreated controls. The profile of total glutathione content was similar to that found for glutathione peroxidase, increasing with the administered doses of the herbicide. Polyamine content has been also studied at the same concentrations of paraquat, showing that intracellular spermidine and spermine pools were negatively affected with paraquat in a dose-response manner, unlike putrescine, which maintained elevated pools at the three concentrations assayed.

Animals↗
PubMed1999

Chemopreventive effect of dietary flavonoid morin on chemically induced rat tongue carcinogenesis.

The modifying effects of dietary exposure of the flavonoid morin on 4-nitroquinoline 1-oxide (4-NQO)-induced tongue tumorigenesis, the activities of phase II detoxifying enzymes glutathione S-transferase (GST) and quinone reductase (QR) in liver and tongue, and cell proliferation activity in tongue were investigated in male F344 rats. At 7 weeks of age, all animals except those treated with morin alone and control group were given 4-NQO (20 ppm) in drinking water for 8 weeks to induce oral neoplasms. Starting 7 days before 4-NQO exposure, experimental groups were fed experimental diets containing morin (100 and 500 ppm) for 10 weeks ("initiation feeding"). Starting 1 week after the cessation of exposure to 4-NQO, other experimental groups given 4-NQO and a basal diet were given experimental diets for 22 weeks ("post-initiation feeding"). At week 32 week, "initiation feeding" of morin caused a significant reduction in the incidence of tongue carcinoma (by 44-100%). "Post-initiation feeding" with morin also significantly decreased the frequency of tongue carcinoma (by 44%). Morin feeding elevated liver GST and QR activities and GST activity in the anterior portion of tongue. Feeding with morin significantly lowered QR activity of the posterior part of the tongue. Dietary exposure to morin significantly decreased the proliferating cell nuclear antigen-positive index in the posterior portion. Also, morin feeding lowered tongue polyamine levels, especially in the "post-initiation feeding" group. Our results indicate that morin acts as a chemopreventive agent against tongue carcinogenesis induced by 4-NQO through modification of detoxifying enzyme activities and/or cell proliferation activities.

4-Nitroquinoline-1-oxide↗
PubMed1990

Polyamines in pancreatic growth.

This chapter reviews available data concerning the role of polyamines in pancreatic growth. Like in many other mammalian cells stimulation of pancreatic proliferation by trophic factors is associated with an early increase in ornithine decarboxylase (ODC) activity with consequent putrescine formation. ODC and putrescine play probably an important role in the initiation but not maintenance of pancreatic growth. The application of the specific ODC inhibitor alpha-difluoromethylornithine (DFMO) alone is not sufficient to judge the role of polyamines in pancreatic growth. For that purpose a combination of substances which inhibit ODC (DFMO) and polyamine oxidase (N1,N4-bisallenylputrescine) and/or S-adenosylmethionine-decarboxylase (SAM-DC) simultaneously has to be investigated. Ideally polyamines from dietary sources and intestinal bacterial flora should be abolished. The uptake of polyamines from the circulation has still to be considered. Studies will be presented proving that though ODC is completely inhibited by DFMO putrescine is still formed via spermidine/spermine N1-acetyltransferase (SAT). The fast increase of ODC in response to growth stimulating factors like cholecystokinin (CCK) is regulated at a pretranslational level by increasing ODC mRNA.

Animals↗