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Results for “Biogenic Polyamines”

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PubMed1990

[Recent progress in polyamine research].

Polyamines are recognized as cell growth factors in relation to cell proliferation, differentiation, regeneration and malignant transformation. Polyamines play an important role in the growth of normal cells like vascular endothelial cells and also exert various effects on the proliferation and metastasis of malignant cells. The recent studies on the biosynthesis have clearly elucidated its mechanism at the gane levels, which reflects to the development of the inhibitors of the polyamine biosynthesis. One of the main purposes of the studies on the various polyamine synthesis inhibitors is for the development of new anti-cancer agents, based on the characteristics of the polyamine functions. The clinical effects of several inhibitors, however, have not been shown to be satisfactory and the reason is now the most important research subject in this field. The measurement of the polyamine contents in biological fluids including urine and blood has been shown to be useful as the tumor marker. The recent studies have indicated that the mechanism of increased secretion of urinary polyamines is due to the release from the degraded cancer cells. The results now stimulated the research which aims to elucidate the usefulness of the measurement of urinary polyamines as the parameters of the sensitivity to the anticancer drugs in patients with cancer.

Biogenic Polyamines↗
PubMed2003

Polyamine dependence of normal cell-cycle progression.

The driving force of the cell cycle is the activities of cyclin-dependent kinases (CDKs). Key steps in the regulation of the cell cycle therefore must impinge upon the activities of the CDKs. CDKs exert their functions when bound to cyclins that are expressed cyclically during the cell cycle. Polyamine biosynthesis varies bicyclically during the cell cycle with peaks in enzyme activities at the G(1)/S and S/G(2) transitions. The enzyme activities are regulated at transcriptional, translational and post-translational levels. When cells are seeded in the presence of drugs that interfere with polyamine biosynthesis, cell cycle progression is affected within one cell cycle after seeding. The cell cycle phase that is most sensitive to polyamine biosynthesis inhibition is the S phase, while effects on the G(1) and G(2)/M phases occur at later time points. The elongation step of DNA replication is negatively affected when polyamine pools are not allowed to increase normally during cell proliferation. Cyclin A is expressed during the S phase and cyclin A/CDK2 is important for a normal rate of DNA elongation. Cyclin A expression is lowered in cells treated with polyamine biosynthesis inhibitors. Thus, polyamines may affect S phase progression by participating in the regulation of cyclin A expression.

Biogenic Polyamines↗
PubMed2007

Polyamine uptake by DUR3 and SAM3 in Saccharomyces cerevisiae.

It has been reported that GAP1 and AGP2 catalyze the uptake of polyamines together with amino acids in Saccharomyces cerevisiae. We have looked for polyamine-preferential uptake proteins in S. cerevisiae. DUR3 catalyzed the uptake of polyamines together with urea, and SAM3 was found to catalyze the uptake of polyamines together with S-adenosylmethionine, glutamic acid, and lysine. Polyamine uptake was greatly decreased in both DUR3- and SAM3-deficient cells. The K(m) values for putrescine and spermidine of DUR3 were 479 and 21.2 mum, respectively, and those of SAM3 were 433 and 20.7 mum, respectively. Polyamine stimulation of cell growth of a polyamine requiring mutant, which is deficient in ornithine decarboxylase, was not influenced by the disruption of GAP1 and AGP2, but it was diminished by the disruption of DUR3 and SAM3. Furthermore, the polyamine stimulation of cell growth of a polyamine-requiring mutant was completely inhibited by the disruption of both DUR3 and SAM3. The results indicate that DUR3 and SAM3 are major polyamine uptake proteins in yeast. We previously reported that polyamine transport protein kinase 2 regulates polyamine transport. It was found that DUR3 (but not SAM3) was activated by phosphorylation of Thr(250), Ser(251), and Thr(684) by polyamine transport protein kinase 2.

Amino Acid Sequence↗
PubMed2001

Modified responses to PGE2 in polyamine biosynthesis by T lymphocytes of gastric- and conjunctiva basal cell-carcinoma patients.

The response to Prostaglandin (PG) E2 of T cells from gastric carcinoma (GC)- and conjunctiva-basal cell carcinoma (conjunctiva-BCC)-bearing patients has been studied in relation to polyamine metabolism. Polyamines are crucial co-factors in cell growth as well as differentiation and many works report that lymphocyte spermine (SP), spermidine (SPD) and putrescine (PUT) levels may be related to tumor proliferation. The present work aims to detect the basal and PGE2 induced concentrations of these polyamines and cAMP, ornithine decarboxylase (ODC), spermine N1-acetyltransferase (SAT) activities of T lymphocytes drawn from patients suffering from GC and conjunctiva-BCC since many carcinomas are characterized by high levels of PGE2. Data obtained from lymphocytes of neoplastic subjects were compared with those derived from PGE2-treated control lymphocytes. Results highlight a very significant increase of all the polyamine metabolites in PGE2-treated T cells from neoplastic patients in respect to the untreated and PGE2-treated control lymphocytes. Therefore, it is conceivable that the PGE2 content increase, often occurring during the epithelial tumour development, may contribute, through enhancement of polyamine metabolism, to tumor progression.

Acetyltransferases↗
PubMed2002

Moderate folate deficiency influences polyamine synthesis in rats.

Spermidine, spermine and putrescine are polyamines, essential growth factors in mammalian cells. Decarboxylated S-adenosylmethionine (SAM) is an essential precursor in the formation of both spermidine and spermine. SAM is formed from methionine through the addition of adenosine. Because 5-methyltetrahydrofolate donates a methyl group to homocysteine to produce methionine, folate deficiency may decrease polyamine synthesis. Weanling male Sprague-Dawley rats were fed an amino acid-defined diet with 2 mg folic acid/kg diet (control) or no added folic acid (test). Blood, liver, brain, jejunum, ileum and colon samples were collected at the end of 5 wk. Compared with controls, rats fed the test diet had a 72% reduction in plasma folate (123.6 +/- 13.1 vs. 34.6 +/- 2.2 nmol/L, P < 0.001) and a 42% reduction in RBC folate (2834.4 +/- 218.3 vs. 1651.8 +/- 75.9 nmol/L, P < 0.001). Hepatic spermidine and spermine in folate-depleted rats were 58 (P < 0.001) and 67% (P < 0.01) higher, respectively, than in controls. Plasma putrescine was 27% higher (P < 0.05) than in controls. The polyamine concentrations of the jejunum, ileum, colon and brain did not differ. This study suggests that mild folate deficiency influences polyamine synthesis, but contrary to our hypothesis, hepatic spermidine and spermine were increased, as was circulating putrescine. This may have occurred for a number of reasons including increased enzyme activity or overcompensation by the betaine-homocysteine transmethylation pathway in the liver. Further study is necessary to clarify interactions between folate and polyamine metabolism and to determine whether polyamines are involved in the damaging effects of folate deficiency.

Animals↗
PubMed1994

Effects of unusual polyamines on phenylalanyl-tRNA formation.

The effects of novel polyamines on aminoacyl-tRNA formation catalyzed by Escherichia coli., Sulfolobus acidocaldarius, and Thermus thermophilus HB8 S-100 extracts were investigated. These effects were diverse and differed depending on the amino acid and the enzyme used. A quaternary polyamine, tetrakis(3-aminopropyl)ammonium, inhibited phenylalanyl-tRNA synthesis catalyzed by the T. thermophilus extract, but not inhibit the other aminoacyl-tRNA formations tested. The inhibition was observed in hybrid reactions where the thermophile tRNA or extract was replaced by its E. coli counterpart, although the quaternary amine did not inhibit Phe-tRNA formation by the E. coli homologous system. Spermine relieved the inhibition of the reaction of thermophile enzyme and tRNA, but not the inhibition of the hybrid reactions. These results suggest that the branched polyamine interacts with both the thermophile enzyme and tRNA(Phe).

Biogenic Polyamines↗
PubMed2006

[Physiological functions of polyamines and regulation of polyamine content in cells].

Polyamines (putrescine, spermidine, and spermine) are essential for normal cell growth. The polyamine level in cells is regulated by biosynthesis, degradation, and transport. The role of antizyme on polyamine biosynthesis and transport in mammalian cells and characteristics of polyamine transport in Escherichia coli and yeast are described briefly in this review. In addition, the effects of polyamines on protein synthesis and the NMDA receptor are outlined. Finally, the correlation between acrolein produced from polyamines by polyamine oxidase and chronic renal failure and brain stroke is summarized. Increased levels of polyamine oxidase and acrolein are good markers of chronic renal failure and brain stroke.

Acrolein↗
PubMed1991

[Polyamine modulation of phosphorylation of channel-forming cytosolic protein in bovine brain].

Phosphorylation of the bovine brain TTX-sensitive cytosolic protein which is similar in several functional properties to the membrane potential-dependent sodium channel has been studied. The results obtained indicate that the cytosolic protein is a substrate for cAMP-dependent phosphorylation. Polyamines at a concentration of 5.0 mmol/l inhibit markedly phosphorylation of the cytosolic protein. Spermine is shown to be the most effective inhibitor. It is suggested that polyamines may modulate the cell sodium channel function.

Animals↗
PubMed1989

Urinary excretion of N1-acetylspermidine and other acetylated and free polyamines in the 1,2-dimethylhydrazine model of experimental rat colon cancer.

1,2-Dimethylhydrazine (DMH) is a potent procarcinogen with selectivity for the colon. Recently, it has been demonstrated that levels of N1-acetylspermidine were elevated 2-3-fold in colonic tumors induced by this agent compared to control tissues. To determine whether alterations in the urinary levels of this acetylated polyamine or other polyamines were useful biochemical markers for colon cancer in this experimental model, rats were given s.c. injections of DMH (20 mg/kg body weight/week) or diluent for 26 weeks. One week after the last injection, control and DMH-treated animals were placed in separate metabolic cages and their urine was collected for 24 h. The urinary levels (expressed as nmol/mg creatinine) of putrescine, spermidine, spermine, N1-acetylspermidine, and N8-acetylspermidine were then analyzed by high-performance liquid chromatography. Animals from each group were then sacrificed and their colons were examined for tumors. The results of these studies demonstrated that the urinary level of N1-acetylspermidine was an excellent biochemical marker for colonic tumors induced by DMH. At 18.3 nmol/mg creatinine, N1-acetylspermidine was 100% sensitive and specific for colon cancer. Moreover, urinary levels of N1-acetylspermidine were better for this purpose than the N1-acetylspermidine/N8-acetylspermidine molar ratio, a marker previously suggested to be more specific for certain cancers than free polyamines.

1,2-Dimethylhydrazine↗
PubMed2004

Molecular dynamics simulation study of oriented polyamine- and Na-DNA: sequence specific interactions and effects on DNA structure.

Molecular dynamics (MD) computer simulations have been carried out on four systems that correspond to an infinite array of parallel ordered B-DNA, mimicking the state in oriented DNA fibers and also being relevant for crystals of B-DNA oligonucleotides. The systems were all comprised of a periodical hexagonal cell with three identical DNA decamers, 15 water molecules per nucleotide, and counterions balancing the DNA charges. The sequence of the double helical DNA decamer was d(5'-ATGCAGTCAG)xd(5'-TGACTGCATC). The counterions were the two natural polyamines spermidine(3+) (Spd(3+)) and putrescine(2+) (Put(2+)), the synthetic polyamine diaminopropane(2+) (DAP(2+)), and the simple monovalent cation Na(+). This work compares the specific structures of the polyamine- and Na-DNA systems and how they are affected by counterion interactions. It also describes sequence-specific hydration and interaction of the cations with DNA. The local DNA structure is dependent on the nature of the counterion. Even the very similar polyamines, Put(2+) and DAP(2+), show clear differences in binding to DNA and in effect on hydration and local structure. Generally, the polyamines disorder the hydration of the DNA around their binding sites whereas Na(+) being bound to DNA attracts and organizes water in its vicinity. Cation binding at the selected sites in the minor and in the major groove is compared for the different polyamines and Na(+). We conclude that the synthetic polyamine (DAP(2+)) binds specifically to several structural and sequence-specific motifs on B-DNA, unlike the natural polyamines, Spd(3+) and Put(2+). This specificity of DAP(2+) compared to the more dynamic behavior of Spd(3+) and Put(2+) may explain why the latter polyamines are naturally occurring in cells.

Base Sequence↗
PubMed1993

The effects of O6-benzylguanine and hypoxia on the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea in nitrosourea-resistant SF-763 cells.

O6-Alkylguanine-DNA alkyltransferase (AGT) activity is associated with resistance of brain tumor cell lines to the cytotoxic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). SF-763 cells exhibit high AGT activity and are resistant to BCNU. In this study, we compared the effects of the AGT inhibitor O6-benzylguanine (BG) on the cytotoxicity of BCNU in oxic and hypoxic SF-763 cells; we also measured AGT activity, ornithine decarboxylase (ODC) activity, and polyamine levels to determine if there was any correlation with cell survival as determined by colony-forming efficiency assay. Exponentially growing monolayer cells were pretreated with 10 microM BG for 2 h under oxic or hypoxic (95% nitrogen/5% CO2) conditions and then exposed to graded concentrations of BCNU for 1 h. BG significantly lowered AGT activity but had no cytotoxic effect in oxic or hypoxic cells; hypoxia alone was not cytotoxic. The cytotoxicity of BCNU was 4 times higher in BG-treated hypoxic cells than in oxic cells treated with BCNU alone; the BCNU doses required for a 1-log cell kill were 75 and 300 microM, respectively. ODC activity was lowered by hypoxia alone but was not significantly affected by BG in either hypoxic or oxic cells. Polyamine levels were not significantly affected by hypoxia or BG. These results indicate that pretreatment with BG dramatically lowers AGT activity and increases the cytotoxicity of BCNU in both oxic and hypoxic SF-763 cells. The mechanism of this enhanced cytotoxicity is apparently unrelated to ODC activity or polyamine levels.

Biogenic Polyamines↗
PubMed1993

Polyamine modulation of excitatory amino acid responses in the rat cortical wedge.

Rat neocortex slices in Mg2+ free buffer show spontaneous discharges which have a constant frequency and are dependent on N-methyl-D-aspartate (NMDA) receptor activation. Spermine increased the frequency of discharges at concentrations below 1 mM, had biphasic effects at 1 mM, and only decreased the frequency of discharges at 3 mM. In contrast, the amplitude of these discharges was only reduced by spermine in a concentration dependent manner (300 microM to 3 mM). Spermidine produced similar effects, but was a less potent inhibitor of discharge frequency and amplitude than spermine. Diethylenetriamine (DET) 300 microM did not significantly inhibit polyamine-induced increases in the discharge frequency. Polyamines inhibited direct depolarizations induced by the glutamate agonists NMDA or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in a concentration and time dependent manner. The data are consistent with two sites of action for polyamines, one enhancing the frequency of NMDA-mediated spontaneous epileptiform discharges and the other inhibiting direct glutamate responses in rat cortex. The slow onset (time to maximal enhancement or inhibition by polyamines greater than 30 min) and lack of reversibility with polyamine removal suggest that these sites are intracellular and/or presynaptic.

Amino Acids↗
PubMed1995

Induction of apoptosis by excessive polyamine accumulation in ornithine decarboxylase-overproducing L1210 cells.

Deregulation of polyamine transport in L1210 cells overexpressing ornithine decarboxylase leads to a lethal accumulation of spermidine. We now provide evidence that over-accumulation of natural and synthetic polyamines, but not putrescine, rapidly induces apoptosis, as shown by hypercondensation of peripheral chromatin and internucleosomal cleavage, followed by nuclear fragmentation. Polyamine oxidation is not responsible for the apoptosis observed. Thus, abnormally high polyamine pools could be an important physiological trigger of apoptosis.

Animals↗
PubMed1996

Platelet-derived growth factor regulates vascular smooth muscle cell proliferation by inducing cationic amino acid transporter gene expression.

Since recent studies demonstrated that platelet-derived growth factor (PDGF) induces vascular smooth muscle cell (SMC) proliferation by stimulating polyamine synthesis, we examined whether the transcellular transport of L-ornithine, the cationic amino acid precursor of polyamines, could regulate the mitogenic response of PDGF. Treatment of SMC with PDGF stimulated DNA and putrescine synthesis, and this was enhanced further by increasing the extracellular concentration of L-ornithine. The potentiating effect of L-ornithine was reversed by the competitive inhibitor of cationic amino acid transport, methyl-L-arginine, or by preventing putrescine formation with alpha-difluoromethylornithine. Cationic amino acid uptake by SMC was Na+-independent and was mediated by both a high and low affinity carrier system. Treatment of SMC with PDGF initially (0-2 h) decreased basic amino acid transport, while longer exposures (6-24 h) progressively increased uptake. Kinetic studies indicated that PDGF-induced inhibition was associated with a decrease in affinity for cationic amino acids, while the stimulation was mediated by an increase in transport capacity. Endogenous PDGF released by collagen-activated platelets likewise up-regulated cationic amino acid transport in SMC. Reverse transcriptase-polymerase chain reaction detected the presence of mRNA encoding two distinct cationic amino acid transporter (CAT) proteins, CAT-1 and CAT-2B. Treatment of SMC with PDGF strongly induced the expression CAT-2B mRNA and modestly elevated the level of CAT-1 mRNA. These results demonstrate that PDGF-induced polyamine synthesis and SMC mitogenesis are dependent on the transcellular transport of L-ornithine. The capacity of PDGF to up-regulate the transport of L-ornithine by inducing the expression of the genes for CAT-1 and CAT-2B may modulate its mitogenic effect by providing SMC with the necessary intracellular precursor for polyamine biosynthesis.

Amino Acid Sequence↗
PubMed1996

Polyamine levels in various tissues of rats treated with 3-hydroxy-4-methoxycinnamic acid and 3,4-dimethoxycinnamic acid.

The effects of 3-hydroxy-4-methoxycinnamic acid (3H4MCA) and 3,4-dimethoxycinnamic acid (3,4DMCA) on body weight, organ weight, and the contents of putrescine, spermidine and spermine in 15 different tissues were examined in rats that had been given these compounds for 5 days. In 3H4MCA-treated rats, the weight of the spleen was significantly increased, while none of the other organs showed any significant changes. A diet containing either 3H4MCA or 3,4DMCA should not be taken by patients bearing cancers in the seminal vesicles, spleen or liver, and a diet containing 3,4DMCA should not be taken by patients bearing cancers in the testis, kidney, muscle, small intestine or brain (cortex) because of the significant increases in polyamines, which are associated with a risk of cancer growth, in these tissues. However, a diet containing 3H4MCA is recommended for the management of cancers in the skeletal muscle (femoral), tongue, small intestine (jejunum), stomach, lung and brain based on reductions in polyamines which stimulate tumor growth. A diet containing 3,4DMCA is also recommended for cancer in the prostate, thymus and stomach for the same reason. In addition, a synergic therapeutic effect for the treatment of cancers in these tissues may be anticipated by a combination of such a diet with anti-cancer drugs which reduce polyamine levels. The metastasis of cancers in these tissues may also be inhibited by the reduction of polyamines by these acids. The ratio of spermidine to spermine was significantly higher in the lung of 3H4MCA-treated rats, and lower in the seminal vesicle, thymus, kidney, heart, tongue, stomach and lung of 3,4DMCA-treated rats, than in control rats. The present experiment indicated that cancer patients should pay careful attention to endogenous polyamines in tissues bearing tumors induced by chemicals in ingesta and anti-cancer drugs, in addition to exogenous polyamines.

Animals↗