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PubMed1993

Diethylglyoxal bis(guanylhydrazone), a potent inhibitor of mammalian S-adenosylmethionine decarboxylase. Effects on cell proliferation and polyamine metabolism in L1210 leukemia cells.

The polyamines are cell constituents essential for growth and differentiation. S-Adenosylmethionine decarboxylase (AdoMetDC) catalyzes a key step in the polyamine biosynthetic pathway. Methylglyoxal bis(guanylhydrazone) (MGBG) is an anti-leukemic agent with a strong inhibitory effect against AdoMetDC. However, the lack of specificity limits the usefulness of MGBG. In the present report we have used an analog of MGBG, diethylglyoxal bis(guanylhydrazone) (DEGBG), with a much greater specificity and potency against AdoMetDC, to investigate the effects of AdoMetDC inhibition on cell proliferation and polyamine metabolism in mouse L1210 leukemia cells. DEGBG was shown to effectively inhibit AdoMetDC activity in exponentially growing L1210 cells. The inhibition of AdoMetDC was reflected in a marked decrease in the cellular concentrations of spermidine and spermine. The concentration of putrescine, on the other hand, was greatly increased. Treatment with DEGBG resulted in a compensatory increase in the synthesis of AdoMetDC demonstrating an efficient feedback control. Cells seeded in the presence of DEGBG ceased to grow after a lag period of 1-2 days, indicating that the cells contained an excess of polyamines which were sufficient for one or two cell cycles in the absence of polyamine synthesis. The present results indicate that analogs of MGBG, having a greater specificity against AdoMetDC, might be valuable for studies concerning polyamines and cell proliferation.

Adenosylmethionine Decarboxylase↗
PubMed1987

Immunocytochemical localization of polyamines in normal and neoplastic cells. Comparisons to the formaldehyde-fluorescamine and o-phthalaldehyde methods.

Polyamines are low molecular weight organic cations, necessary for cell proliferation and implicated in numerous biochemical events. Their light microscopical distribution has previously been studied by the use of two fluorescence cytochemical methods. With the aid of an antibody recognizing the two main polyamines, spermidine and spermine, we now report on their immunocytochemical localization in animal tissues. Polyamine immunocytochemistry was found to require very well controlled conditions of fixation in order to prevent diffusion, loss and redistribution of endogenous polyamines. Moreover, in certain cellular compartments, polyamine immunoreactivity was masked by proteins, necessitating proteolytic pretreatment of sections prior to staining. The fluorescence cytochemical methods, employing low molecular weight reagents, did not require such unmasking. The results of the optimized immunocytochemical procedure were in complete agreement with the results obtained by the fluorescence cytochemical methods. Although fluorescence cytochemistry, is simpler and quicker to perform than immunocytochemistry, the latter technique may be extended to studies of polyamines at the ultrastructural level.

Animals↗
PubMed1985

Polyamines and estrogen control of growth of the NMU-induced rat mammary tumor.

Recent in vitro evidence suggests that polyamines play an important role in the growth of the N-nitrosomethyl-urea (NMU)-induced rat mammary tumor, and that they may be involved in mediating the effect of estrogens on tumor growth. In support of this hypothesis, we here show that inhibition of polyamine biosynthesis with alpha-difluoromethyl-ornithine (DFMO) blocks the mitogenic effect of estradiol-17 beta (E2) added to NMU-mammary tumors grown in soft agar in the presence of the antiestrogen tamoxifen (Tam). Exogenous polyamine administration reversed the inhibitory effect of DFMO and restored E2 action. Administration of polyamine inhibitors to NMU-tumor-bearing rats induced significant inhibition of tumor growth, although tumor ornithine decarboxylase (ODC) was not consistently suppressed. Under our experimental conditions, such treatment did not potentiate the antitumor effect of Tam. Tam alone was found to suppress tumor ODC, suggesting a possible involvement of the polyamine pathway in its antitumor action. These data suggest that the polyamines may play an important role in the hormonal control of the growth of this experimental breast cancer.

Animals↗
PubMed1987

Polyamines and the synthesis of estradiol-regulated growth factors in rat mammary cancer in culture.

We have recently provided evidence to suggest that the polyamine pathway plays an essential role in the expression of the growth-promoting effect of estradiol (E2) regulated growth factors in the N-nitrosomethylurea (NMU) induced rat mammary tumor cultured in vitro in the soft agar clonogenic assay. To further explore the interaction between the polyamine pathway and autocrine control of tumor growth by E2, we tested whether, in our system, polyamines play a role in the synthesis of E2-regulated growth factors. Conditioned medium (CM) obtained from tumors treated with E2 and the polyamine biosynthesis inhibitor alpha-difluoromethyl-ornithine (DFMO) (1 mM) no longer exhibited the colony-stimulating effect which was consistently observed with E2-CM. Such growth promoting activity was restored in a dose-dependent fashion with CM obtained from tumors treated with E2, DFMO, and increasing concentrations of spermidine (from 1 to 100 microM). Conditioned medium obtained from tumors treated with DFMO with and without spermidine in the absence of E2 had no discernible effects on colony formation. The colony stimulating effect of the CM employed could not be accounted for by the contaminating presence in the media of E2, DFMO, or polyamines. These results indicate that, in our system, the polyamine pathway plays an important role in the synthesis of E2-regulated growth factors.

Animals↗
PubMed1988

Role of polyamines in the growth of hormone-responsive experimental breast cancer in vivo.

We have provided evidence for a critical role of polyamines in the growth of the hormone-responsive N-nitrosomethyl-urea (NMU)-induced rat mammary tumor in vitro. The present experiments were designed to test whether polyamines are involved in the growth of this experimental tumor in vivo. To test this hypothesis, groups of rats bearing NMU-induced mammary cancers were randomly allocated to receive no treatment or escalating doses of the polyamine biosynthesis inhibitor alpha-difluoromethyl-ornithine (DFMO) (0.5%, 1%, 2%, 3% in drinking water). DFMO inhibited tumor growth in a dose-dependent fashion and consistently reduced tumor putrescine level. To evaluate the time dependency of this effect, additional groups of rats received either no treatment or 2% DFMO for 3, 7, 14, and 21 days. At all times DFMO suppressed tumor putrescine level as well as spermidine to spermine ratio. Finally, exogenous administration of putrescine (200 mg/kg/i.p./day x 21 days) given concomitantly with DFMO restored tumor growth, partially repleted tumor putrescine level, and raised the spermidine to spermine ratio to control levels. Putrescine, given alone, had no significant effect on either tumor polyamine levels or tumor growth. Except for modest weight loss, no major toxicity was encountered. These results indicate that polyamines play an important role in the growth of the NMU rat mammary tumor in vivo. The interaction between polyamines and hormones in supporting NMU mammary tumor growth in vivo remains to be elucidated.

Animals↗
PubMed1993

Polyamines, diamine oxidase, and ornithine decarboxylase activity in colorectal cancer and in normal surrounding mucosa.

We investigated the polyamine levels [putrescine (Put), spermidine (Spd), and spermine (Spm)] and their metabolism by simultaneously considering the ornithine decarboxylase (ODC) and diamine oxidase (DAO) activities in human colorectal cancer and in normal surrounding tissue. Single and total polyamine levels were significantly higher in the neoplastic tissue than in the surrounding mucosa from the same patients. Furthermore, the ODC activity was significantly higher and the DAO activity significantly lower in the neoplastic tissue than in the surrounding mucosa. Polyamine levels and enzymatic activities did not correlate with the clinical and histologic characteristics of patients. In normal tissue samples, no correlation was found between single and total polyamine levels and enzymatic activities (both DAO and ODC). On the contrary, in colorectal neoplastic samples, significant and positive correlations were found between the levels of total polyamines, Spd, and Spm and the ODC activity. In the same specimens, DAO activity was related to Spd levels and the Spd/Spm ratio, but, in those cases, the correlation was negative. Thus, our findings suggest that, during the neoplastic growth of the colorectal mucosa, the balance between polyamine degradation and biosynthesis is disengaged from the control exerted by the two enzymes.

Adenocarcinoma↗
PubMed1995

Low density lipoprotein receptors and polyamine levels in human colorectal adenocarcinoma.

The low density lipoprotein receptor (LDLR) is a cell surface protein that binds with LDL, providing the cell with cholesterol for new membrane synthesis. Rapidly growing cells have high numbers of LDLRs, and these proteins have also been detected in neoplastic samples of human colorectal mucosa. Polyamines, putrescine, spermidine, and spermine, play an important role in cellular growth, and studies on colorectal cancers have demonstrated higher polyamine levels in neoplastic mucosa samples than in surrounding mucosa. The aim of this study was to investigate LDLR and polyamine levels in the neoplastic tissue of 43 patients (28 males and 15 females) with colorectal adenocarcinoma, using enzymatic immunoassay and high performance liquid chromatography, respectively. Specimens of neoplastic mucosa were considered LDLR-positive or LDLR-negative when the amount of bound human anti-LDLR antibody detected was equal or higher or lower than the cut-off value (0.5 ng of bound anti-LDLR Ab/mg protein), respectively. Twenty-one subjects were LDLR-positive and 22 LDLR-negative. Polyamine levels (nmol/g tissue) were higher in LDLR-positive specimens; this increase was significant for total polyamines (P < 0.05). These findings, reporting the presence of increased polyamine content in LDLR-positive colorectal neoplastic specimens, suggest an association between LDLR levels and gastrointestinal neoplastic proliferative activity.

Adenocarcinoma↗
PubMed1987

The effects of some polyamines on putative behavioural indices of mesolimbic versus striatal dopaminergic function.

The presence of polyamines in the brain, together with the previous reports of a structural similarity with neuroleptics, has led to the hypothesis that polyamines may have a modulatory role in the control of cerebral dopamine function. In this study, the effects of two polyamines, spermine and spermidine, were therefore tested on indices of dopamine-mediated behaviour in rats and mice. Spermine and spermidine caused a dose-dependent inhibition of mouse spontaneous climbing behaviour and wheel running at doses between 5 and 40 mg/kg IP but failed to cause catalepsy in the rat or to antagonise the stereotyped behaviour induced by apomorphine. When polyamines were given by intracerebral injection a similar regional selectivity was seen. Both spermine and spermidine (5-20 micrograms) when given bilaterally into the nucleus accumbens inhibited the hyperactivity caused by amphetamine injected into the same nucleus. However, when injected into the rat corpus striatum, neither polyamine was able to initiate any asymmetry or circling either spontaneously or after apomorphine injection IP. These results indicated a selective action of polyamines on mesolimbic dopamine behaviour. Possible implications for the understanding of psychosis and future work are suggested.

Amphetamine↗
PubMed1999

Polyamines. An overview.

The polyamines spermine, spermidine, and putrescine are small organic molecules one or more of which are present in all living organisms. Many natural products contain polyamine residues. Polyamines are synthesized by a highly regulated pathway from arginine or ornithine and also can be transported in and out of cells. Polyamines are degraded to a variety of compounds the functions of which are largely unknown. Polyamines influence the transcriptional and translational stages of protein synthesis, stabilize membranes, and, in mammalian systems, modulate neurophysiological functions and may act as intracellular messengers. However, at the molecular level the mode of action of the polyamines is largely unknown.

Animals↗
PubMed1995

High performance liquid chromatography separation and simultaneous fluorometric detection of trace amount of polyamines in cell culture media.

A highly sensitive and precise method for the determination of the polyamines (including putrescine, spermidine and spermine) in cell culture media is described. The samples were concentrated by C18 column and the polyamines were converted to fluorometric derivatives with DNS-Cl. The polyamine derivatives were then completely separated by HPLC and determined by simultaneous fluorometric detection. The CV of intragroup and intergroup were 2.49%-4.26% and 4.29%-5.16%, respectively. The rate of recovery was 103%-99%. There was trace amount of polyamines detected by this method in the media of F12, 8900, RPMI-1640, DMEM and M199 even without incubation with cells. So this method can be used for detecting the changes of polyamines in a medium before and after incubation with cells. It is helpful for the researches on the regulation of cell proliferation by polyamines.

Animals↗
PubMed2006

Akt-mediated GSK-3beta inhibition prevents migration of polyamine-depleted intestinal epithelial cells via Rac1.

The rapid migration of intestinal epithelial cells (IEC) is important for the healing of mucosal wounds. We have previously shown that polyamine depletion inhibits migration of IEC-6 cells. Akt activation and its downstream target GSK-3beta have been implicated in the regulation of migration. Here we investigated the significance of elevated phosphatidylinositol 3-kinase (PI3K)/Akt signaling on migration of polyamine-depleted cells. Polyamine-depleted cells had high Akt (Ser473) and GSK-3beta (Ser9) phosphorylation. Pretreatment with 20 microM LY294002 (PI3K inhibitor) for 30 min inhibited phosphorylation of Akt, increased migration by activating Rac1 in polyamine-depleted IEC-6 cells, and restored the actin structure similar to that in cells grown in control medium. Treatment of cells with a GSK-3beta inhibitor (AR-A014418) altered the actin cytoskeleton and inhibited migration, mimicking the effects of polyamine depletion. Thus, our results indicate that sustained activation of Akt in response to polyamine depletion inhibits migration through GSK-3beta and Rac1.

Actins↗
PubMed2006

Platinum drug effects on the expression of genes in the polyamine pathway: time-course and concentration-effect analysis based on Affymetrix gene expression profiling of A2780 ovarian carcinoma cells.

PURPOSE: As a follow-up to our previous findings that platinum drugs induce a key enzyme in polyamine catabolism, gene expression profiling and mathematical modeling were used to define the effects of cisplatin and oxaliplatin on the expression of polyamine metabolic pathway genes in A2780 human ovarian carcinoma cells. METHODS: Time-course and concentration-effect experiments were each carried out with cisplatin or oxaliplatin in two separate experiments and cells subjected to gene expression profiling using Affymetrix array technology. Time-course data were modeled using exponential increase and decrease models. Concentration-effect data were modeled using a four parameter Hill model. RESULTS: Gene expression profiling of human ovarian carcinoma A2780 cells after exposure to either cisplatin or oxaliplatin indicates that the expression of several genes involved in polyamine pathway is affected by the platinum drugs. Mathematical/Statistical modeling of the data from time-course and concentration-effect experiments of gene expression from nine polyamine pathway genes represented on the HGU95Av2 chip, indicates that three biosynthetic pathway genes (SAMDC, ODC1 and SRM) are down-regulated and one catabolic pathway gene (SSAT) is up-regulated. Expression changes were similar for different probesets for a given gene on the array. Studies on the induction of SSAT by platinum drugs suggested by the Affymetrix data have been previously validated from this laboratory (Hector et al. in Mol Cancer Ther 3:813-822, 2004). Here, the effects of oxaliplatin exposure on SAMDC and ODC observed by Affymetix are validated with real time QRT-PCR. CONCLUSION: The data indicate a concerted effect of platinum drugs on the polyamine metabolic pathway with down-regulation in the expression of several enzyme genes involved in biosynthesis and many-fold up-regulation in expression of SSAT, an acetylating enzyme gene that is critically involved in polyamine catabolism and export.

Acyltransferases↗
PubMed2005

Polyamines are essential for the synthesis of 2-ricinoleoyl phosphatidic acid in developing seeds of castor.

The major fatty acid component of castor (Ricinus communis L.) oil is ricinoleic acid (12-hydroxy-cis-9-octadecenoic acid), and unsaturated hydroxy acid accounts for >85% of the total fatty acids in triacylglycerol (TAG). TAG had a higher ricinoleate content at position 2 than at positions 1 and 3. Although lysophosphatidic acid (LPA) acyltransferase (EC 2.3.1.51), which catalyzes acylation of LPA at position 2, was expected to utilize ricinoleoyl-CoA preferentially over other fatty acyl-CoAs, no activity was found for ricinoleoyl-CoA in vitro at concentrations at which other unsaturated acyl-CoAs were incorporated rapidly. However, activity for ricinoleoyl-CoA appeared with addition of polyamines (putrescine, spermidine, and spermine), while polyamines decreased the rates of incorporation of other acyl-CoAs into position 2. The order of effect of polyamines on LPA acyltransferase activity was spermine > spermidine >> putrescine. At concentrations of spermine and spermidine of >0.1 mM, ricinoleoyl-CoA served as an effective substrate for LPA acyltransferase reaction. The concentrations of spermine and spermidine in the developing seeds were estimated at approximately 0.09 and approximately 0.63 mM, respectively. These stimulatory effects for incorporation of ricinoleate were specific to polyamines, but basic amino acids were ineffective as cations. In contrast, in microsomes from safflower seeds that do not contain ricinoleic acid, spermine and spermidine stimulated the LPA acyltransferase reaction for all acyl-CoAs tested, including ricinoleoyl-CoA. Although the fatty acid composition of TAG depends on both acyl-CoA composition in the cell and substrate specificity of acyltransferases, castor bean polyamines are crucial for incorporation of ricinoleate into position 2 of LPA. Polyamines are essential for synthesis of 2-ricinoleoyl phosphatidic acid in developing castor seeds.

Acetyl Coenzyme A↗
PubMed2004

Polyamines and cancer: minireview article.

The naturally occurring polyamines, spermine, spermidine and the diamine putrescine are widespread in nature. They have been implicated in growth and differentiation processes. Polyamines accumulate in cancerous tissues and their concentration is elevated in body fluids of cancer patients. Assays of urinary and blood polyamines have been used to detect cancer and to determine the success of therapy. Drugs which inhibit the synthesis of polyamines can prevent cancer and may also be used for therapeutic purposes. Ornithine decarboxylase, which catalyzes the rate limiting step in polyamine synthesis, can serve as a marker of proliferation. Recently, a new in vitro chemosensitivity test, based on the disappearance of ornithine decarboxylase in drug-treated cancer cells has been developed. The increasing interest in polyamines and their physiological functions may lead to a more extensive application of these compounds or their derivatives in cancer diagnosis and treatment.

Antineoplastic Agents↗
PubMed2004

The biological functions of polyamine oxidation products by amine oxidases: perspectives of clinical applications.

The polyamines spermine, spermidine and putrescine are ubiquitous cell components. If they accumulate excessively within the cells, due either to very high extracellular concentrations or to deregulation of the systems which control polyamine homeostasis, they can induce toxic effects. These molecules are substrates of a class of enzymes that includes monoamine oxidases, diamine oxidases, polyamine oxidases and copper containing amine oxidases. Polyamine concentrations are high in growing tissues such as tumors. Amine oxidases are important because they contribute to regulate levels of mono- and polyamines. These enzymes catalyze the oxidative deamination of biogenic amines and polyamines to generate the reaction products H2O2 and aldehyde(s) that are able to induce cell death in several cultured human tumor cell lines. H2O2 generated by the oxidation reaction is able to cross the inner membrane of mitochondria and directly interact with endogenous molecules and structures, inducing an intense oxidative stress. Since amine oxidases are involved in many crucial physiopathological processes, investigations on their involvement in human diseases offer great opportunities to enter novel classes of therapeutic agents.

Animals↗
PubMed2005

Decreased apoptosis in polyamine depleted IEC-6 cells depends on Akt-mediated NF-kappaB activation but not GSK3beta activity.

The PI3-kinase/Akt pathway promotes cell survival in many different cell types including intestinal epithelial cells. Increased AKT activation in polyamine depleted intestinal epithelial cells correlated well with the decrease in TNF-alpha-induced apoptosis. Increased Akt activation and GSK3beta (Ser 9) phosphorylation without significant effect on Bad (Ser136) phosphorylation indicate that Akt-mediated protection is independent of Bad phosphorylation but may depend on GSK3beta. Pretreatment of polyamine-depleted cells with LY294002 increased caspase-9 and caspase-3 activation and decreased basal levels of GSK-3beta phosphorylation. Inhibition of GSK3beta activity using AR-A014418 or lithium chloride or siRNA-mediated downregulation of its expression had no effect on apoptosis. Inhibition of PI3-kinase and over-expression of dominant negative Akt (DN-AKT), significantly increased apoptosis in polyamine depleted cells. DN-Akt expression reversed the protective effect of polyamine depletion on apoptosis. DN-Akt, as well as the PI3-kinase inhibitors, prevented Akt activation and subsequent translocation of NF-kappaB to the nucleus. Constitutively active Akt (CA-AKT) expression increased resistance to TNF-alpha-induced apoptosis. Constitutively active-Akt expression increased nuclear staining of NF-kappaB. Moreover, polyamine depletion of DN-Akt cells prevented basal and TNF-alpha-induced IkappaBalpha phosphorylation. Prevention of NF-kappaB activation in DN-IkappaBalpha-transfected cells increased apoptosis in control cells and restored it in polyamine-depleted cells to control levels. These data indicate that Akt regulates the mitochondrial pathway, preventing activation of caspase-9 and thereby caspase-3 via NF-kappaB and these effects are independent of GSK-3beta activity.

Androstadienes↗
PubMed1983

Effect of polyamines on palmitoyl-coenzyme A-caused inhibition of glucose-6-phosphate dehydrogenase from baker's yeast.

Aliphatic polyamines reversed the inhibition of baker's yeast glucose-6-phosphate dehydrogenase by palmitoyl-CoA. The reversal effects of the polyamines on the inhibition were related not only to the number of amino (imino) groups but also to the carbon chain length of polyamine. The relieving constant (Kr) was calculated to determine the absolute concentration of each examined polyamine required to relieve the enzyme from the inhibition. A smaller Kr value indicates a stronger relieving activity. An ethylamine derivative with a large number of amino groups was more effective in reversing the palmitoyl-CoA inhibition. The Kr values of long-chain aliphatic diamines, triamines, and tetramines were smaller than those of short-chain ones. However, n-butylamine and ornithine, composed of four carbons like putrescine, had markedly larger Kr values than putrescine. Substitution of one or two amino groups by carboxyl or hydroxyl groups also appeared to relieve the enzyme from the inhibition. These results suggest that the reversal effect on palmitoyl-CoA inhibition is one of the important roles of polyamines. Furthermore, it is possible that the interaction of palmitoyl-CoA and polyamines physiologically regulates the pentose monophosphate cycle in baker's yeast.

Acyl Coenzyme A↗
PubMed1978

Influence of polyamines on the activity of DNA polymerase I from Escherichia coli.

The influence of polyamines on the various activities of DNA polymerase I from Escherichia coli (EC 2.7.7.7) has been investigated. For all high molecular weight DNAs spermine and spermidine caused up to 80% inhibition when present in high concentrations, i.e. above 1 mM for spermine and 2 mM for spermidine. In the presence of low concentrations of polyamines a small activation was seen for some DNAs. The diamines cadaverine and putrescine had little influence on the rate of synthesis with natural occurring DNAs. In the case of d(A--T)n the activation/inhibition was found to be markedly dependent on the molecular weight of the samples used. With a low molecular weight DNA, 5.6 S, addition of spermidine resulted in up to 3-fold stimulation of activity. The activation was dependent on the concentration of MgCl2 and ionic strength; increasing concentration of these gave a decrease in the degree of activation. Polyamines also had a dramatic effect on the rate of synthesis using the homopolymers (dA)n . (dT)10 and (rA)n . (dT)10 . (20:1) as primers. Putrescine, in particular, increased the activity up to 10-fold with (rA)n . (dT)10 and somewhat less for (dA)n . (dT)10. The apparent Km for the primer (rA)n . (dT)10 decreased approx. 35-fold in the presence of 6.6 mM putrescine. There was no influence on the apparent Km for dTTP. The influence of polyamines on both the 5' leads to 3' and 3' leads to 5' nuclease activity was also investigated. Inhibition of nuclease activity was observed in the presence of polyamines, particularly with spermine. Thus with d(A--T)n and T7 DNA as substrates addition of 0.7 mM spermine resulted in almost complete inhibition of the activity. The dramatic inhibition observed with high concentrations of spermine (spermidine) both in the case of polymerizing and nuclease activity is thought to be due to polyamine-induced aggregation of DNA molecules.

Cadaverine↗