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PubMed2002

Biochemical effects and growth inhibition in MCF-7 cells caused by novel sulphonamido oxa-polyamine derivatives.

The novel polyamine derivatives sulphonamido oxa-spermine (oxa-Spm) and sulphonamido oxa-spermidine (oxa-Spd) exhibited rapid cytotoxic action towards MCF-7 human breast cancer cells with IC50 values of 4.35 and 6.47 pM, respectively, after 24-h drug exposure. Neither compound is a substrate of serum amine oxidase. Both oxa-Spm and oxa-Spd caused cell shrinkage, as determined by phase-contrast microscopy. After incubation with 10 microM of either compound for 8 h, the cells underwent chromatin condensation and nuclear fragmentation. However, no clear DNA ladder was obtained by electrophoresis. The sulphonamido oxa-polyamine derivatives and especially oxa-Spd enhanced the activity of polyamine oxidase (PAO), an enzyme capable of oxidising N1-acetylated spermine and spermidine to spermidine and putrescine, respectively, generating cytotoxic H2O2 and 3-acetamidopropanal as by-products. The intracellular polyamine content was only marginally reduced in response to drug treatment. In conclusion, our data show that these novel sulphonamido oxa-polyamine derivatives possess high cytotoxic activity against MCF-7 cells and indicate that induction of PAO may mediate their cytotoxicity via apoptosis.

Amine Oxidase (Copper-Containing)↗
PubMed2006

Polyamines in renal failure.

The levels of polyamines (putrescine, spermidine and spermine) and polyamine oxidase in plasma of patients with chronic renal failure were determined. The level of putrescine was increased but the level of spermine was decreased in the plasma of these patients. The patients also had increased plasma polyamine oxidase activity leading to increased degradation of spermine. As acrolein was a major toxic compound produced from spermine by polyamine oxidase, the levels of free and protein-conjugated acrolein in plasma were also measured. Acrolein levels were enhanced in plasma of patients with chronic renal failure. The accumulated acrolein found as protein conjugates was equivalent to 170 microM, which was about 5-fold higher than in plasma of normal subjects. It was found that acrolein is mainly produced by spermine oxidase in plasma. An increase in putrescine, spermine oxidase and acrolein in plasma was observed in all cases such as diabetic nephropathy, chronic glomerulonephritis and nephrosclerosis. After patients with chronic renal failure had undergone hemodialysis, their levels of plasma polyamines, spermine oxidase and acrolein returned towards normal. It is likely that acrolein produced from spermine accumulates in the blood due to decreased excretion into urine and may function as a uremic "toxin".

Acrolein↗
PubMed1991

Polyamine metabolism in some helminth parasites.

Polyamine levels of some helminth parasites were analyzed by reverse phase HPLC of benzoyl derivatives. Setaria cervi, Acanthocheilonema viteae, Hymenolepis nana, H. diminuta, and Ascaridia galli contained higher levels of spermine than spermidine while in Ancylostoma ceylanicum and Nippostrongylus brasiliensis the spermidine levels were higher than spermine; putrescine was either absent or present in minor quantities. The enzymes of polyamine biosynthesis viz., ornithine decarboxylase, S-adenosyl methionine (SAM)-decarboxylase, and arginine decarboxylase were present in very low to negligible amounts in all the parasites examined. A. ceylanicum exhibited high activity of ornithine amino transferase (OAT) and catalyzed appreciable decarboxylation of ornithine. The ornithine decarboxylating activity of A. ceylanicum was localized in the particulate fraction containing mitochondria, not inhibited by alpha-difluoromethyl ornithine, the specific inhibitor of ornithine decarboxylase (ODC), but inhibited in the presence of glutamate, suggesting the involvement of mitochondrial OAT rather than a true ODC in ornithine decarboxylation in this parasite. Significant activity of polyamine oxidase was also detected in helminth parasites. The absence of polyamine biosynthesizing enzymes in helminth parasites suggests their dependence on hosts for uptake and interconversion of polyamines, providing a potential target for chemotherapy.

Ancylostoma↗
PubMed1991

Polyamine-dependent production of lymphocytotoxic levels of ammonia by human peripheral blood monocytes.

The activity of polyamine oxidase down-regulates IL-2 production in cultures of peripheral blood mononuclear cells. Monocytes are the main source of this enzymatic activity which generates ammonia. We therefore assessed the production of ammonia by human monocytes. We report that human peripheral blood monocytes produce and secrete ammonia and that this activity peaks after 2 days of incubation in vitro. Ammonia production can be suppressed by inhibiting polyamine biosynthesis and polyamine oxidation; thus, the activity of polyamine oxidase in human monocytes generates ammonia. Ammonia production could serve as a measure of polyamine oxidase activity in human monocytes. The levels of ammonia produced in our system reduce human lymphocyte viability. Therefore, ammonia can be added to the list of macrophage products having cytotoxic and immunosuppressive potential.

Adult↗
PubMed1980

Acetylation of spermidine in polyamine catabolism.

Treatment with thioacetamide (150 mg/kg) was used to enhance polyamine metabolism in rat liver. The increased uptake and catabolism of [14C]spermine and the changes of putrescine, spermidine and spermine concentrations indicated enhanced polyamine turnover rates. The increase of hepatic putrescine concentration was accompanied by an increase of monoacetylputrescine and N1-monoacetylspermidine concentration. In control animals, the latter compound was below detection levels. Thioacetamide treatment also enhanced putrescine excretion, which again was concomitant with an increased excretion of N1-acetylspermidine. The close time-dependent correlation between induced putrescine formation and enhanced formation of N1-acetylspermidine at a time when liver spermidine and spermine concentrations are not changed, favors the notion that acetylation is an essential step in polyamine degradation and elimination. The increase of polyamine oxidase and decrease of acetylpolyamine deacetylase activities in the liver of thioacetamide-treated rats is in line with an increased polyamine turnover, but these enzymes, although essential, are not rate-limiting in the catabolic reactions.

Acetamides↗
PubMed1995

Diamine and polyamine oxidase activities in phytohaemagglutinin-induced growth of rat small intestine.

The activities of diamine and polyamine oxidases, two enzymes of polyamine catabolism, were studied in hyperplastic growth of rat small intestine induced by phytohaemagglutinin. This growth, evaluated by the elongation of Lieberkühn's crypts, was more extensive in the proximal than in the distal parts of the gut. The activity of diamine oxidase was significantly reduced in the proximal (70%), medial (45%) and the distal (25%) parts. The activity of polyamine oxidase was doubled. The concentrations of putrescine, cadaverine and spermidine were significantly elevated in the three intestinal parts studied, whereas those of histamine and spermine were unchanged. It appears that changes in the activities of diamine and polyamine oxidases may contribute to the increased putrescine content, which is necessary to maintain active polyamine turnover for sustaining growth of the gut.

Amine Oxidase (Copper-Containing)↗
PubMed1991

The growth of MAT-LyLu rat prostatic adenocarcinoma can be prevented in vivo by polyamine deprivation.

The combination of inhibitors of ornithine decarboxylase and polyamine oxidase, and of antibiotics suitable for the (partial) decontamination of the gastrointestinal tract, with a polyamine deficient diet, is responsible for the almost complete inhibition of the growth of MAT-LyLu prostatic adenocarcinoma. In the tumor-bearing animals, erythrocyte spermidine levels were reduced, but spermine concentrations were increased. As has been previously observed, the increase in erythrocyte spermine level was associated with an enhancement of malignant cell death. Adriamycin administration did neither diminish tumor growth, nor potentiate the antitumor effect of polyamine deprivation treatment. Interruption of the polyamine deprivation treatment was accompanied by a significant enhancement of tumor growth. Since polyamine deprivation causes only reversible growth inhibition, it seems not appropriate as a monotherapy.

Adenocarcinoma↗
PubMed1995

Evaluation of the significance of polyamines and their oxidases in the aetiology of human cervical carcinoma.

The risk of cancer of the cervix is linked with sexual behaviour. Although infectious agents such as human papillomaviruses (HPVs) are implicated, these alone may be insufficient to induce the disease. We have investigated the potential role of oxidation products of the polyamines spermine and spermidine and the diamine putrescine in seminal plasma (SP) as co-factors in the development of cervical cancer. These amines are oxidised by polyamine oxidase (PAO) and diamine oxidase (DAO) to generate oxygen radicals and hydrogen peroxide, reactive aldehydes and acrolein, which are likely to exert local mutagenic, cytotoxic and immunosuppressive effects in vivo. Using a chemiluminescence assay, we determined the levels of these amines in 187 samples of SP. Spermine plus spermidine, as substrates for PAO, were present in a range equivalent to 0-4.8 mg ml-1 spermine. Putrescine, as a substrate for DAO, was detectable in only 4 of 40 samples assayed (range 0-168 micrograms ml-1) and constitutes a minor component of the oxidisable content of SP. Cervical mucus (126 samples) was assayed for the presence of PAO and DAO. Both enzymes were present in 14.3% of the samples, PAO only in 21.4%, DAO only in 15.1% and neither enzyme in 49.2%. PAO levels ranged from 0 to 0.828 pmol peroxide generated min-1 mg-1 mucus and DAO levels ranged from 0 to 7.0 pmol peroxide generated min-1 mg-1 mucus. These results suggest that sexual activity in the absence of physical barrier contraception may lead to the generation of mutagenic and immunosuppressive polyamine oxidation products within the female genital tract. We thus propose that women with high levels of PAO and/or DAO in their cervical mucus may be at increased risk of cervical cancer, especially if the male partner's SP shows high polyamine levels. HPV infection may synergise with the effects of polyamine oxidation by suppressing apoptosis in keratinocytes carrying potentially oncogenic mutations, leading to the survival and proliferation of transformed cells in the cervix.

Adolescent↗
PubMed1987

Oxidized polyamines and the growth of human vascular endothelial cells. Prevention of cytotoxic effects by selective acetylation.

The responses of human umbilical-vein vascular endothelial cells in culture to the naturally occurring polyamines spermine, spermidine and putrescine, their acetyl derivatives and oxidation products were examined. In the absence of human polyamine oxidase, exposure of cells to polyamines (up to 160 microM) had no adverse effects. In the presence of polyamine oxidase, spermine and spermidine were cytotoxic, but putrescine was not. Acetylation of the aminopropyl group of spermidine or both aminopropyl groups of spermine prevented this cytotoxicity. The amino acids corresponding to the polyamines, representing a further stage of oxidation, were also without effect. The cytotoxic effects were irreversible. Use of bovine serum amine oxidase in place of the human enzyme gave qualitatively similar results.

Acetylation↗
PubMed1991

Polyamine catabolism in rodent and human cells in culture.

N1-Acetylspermidine (N1AcSpd) accumulates in late exponential phase, or after certain stresses such as heat shock, in both human tumour (A549) and rodent (HTC, CHO) cells, grown in medium containing an inhibitor of the FAD-dependent polyamine oxidase (PAO). Inhibition of PAO has little effect on cell growth or on the cellular content of the major polyamines, putrescine, spermidine or spermine, found in proliferating cells in culture, but decreases cellular putrescine content in heat shocked cells. Putrescine and spermidine are generated when N1AcSpd or N1-acetylspermine (N1AcSpm) respectively is added to either human or rodent cells depleted of the former amines by alpha-difluoromethylornithine. N1AcSpm is formed in polyamine-depleted human A549 cells when N1AcSpd is added to cultures treated with the PAO inhibitor. This reaction does not occur in either rodent line, suggesting that N1AcSpd can be converted directly into N1AcSpm in human, but not rodent, cells under specific conditions. The data presented demonstrate that a variety of human and rodent cells express PAO activity and catabolize polyamines by a mechanism which includes PAO. PAO activity is of little consequence to proliferating A549, HTC or CHO cells in culture, but does produce new putrescine in both late-exponential-phase and heat-shocked cells. These findings suggest that polyamine catabolism is part of a general response of both rodent and human cells to a variety of environmental and physiological stresses.

Animals↗
PubMed1999

Novel gating mechanism of polyamine block in the strong inward rectifier K channel Kir2.1.

Inward rectifying K channels are essential for maintaining resting membrane potential and regulating excitability in many cell types. Previous studies have attributed the rectification properties of strong inward rectifiers such as Kir2.1 to voltage-dependent binding of intracellular polyamines or Mg to the pore (direct open channel block), thereby preventing outward passage of K ions. We have studied interactions between polyamines and the polyamine toxins philanthotoxin and argiotoxin on inward rectification in Kir2.1. We present evidence that high affinity polyamine block is not consistent with direct open channel block, but instead involves polyamines binding to another region of the channel (intrinsic gate) to form a blocking complex that occludes the pore. This interaction defines a novel mechanism of ion channel closure.

Animals↗
PubMed1985

Immunoregulatory activities of human trophoblasts mediated by polyamine complexes.

In a previous publication we described the presence in human placenta (HP) of immunosuppressive factors inhibiting the lymphoproliferative responses to mitogen. The results of further study reported herein indicate that the substance involved is of a syncytiotrophoblastic origin, that it is thermostable to 100 degrees C for 1 hr, and of low molecular weight, i.e. 3,500. It was defined as a polyamine conjugate with nucleic acids. Trophoblast cell extracts lost their immunosuppressive ability after heating in cultures of human lymphocytes supplemented with 5% autologous serum. These effects were, however, preserved both in cultures assayed in 5% fetal calf serum and in those to which purified polyamine oxidase (PAO) was added to autologous serum. Trophoblast cell extract was found to contain polyamine oxidases. Placental PAO can be inhibited by quinacrine a typical inhibitor of flavoprotein enzymes but not by isoniazid, an inhibitor of pyridoxal enzymes; this would suggest that the enzymes in human placenta are of a tissular rather than seric origin. The implication of these observations is that immunosuppression is mediated by oxidative products issued from an interaction between polyamine and polyamine oxidase in the syncytiotrophoblast cytosol. This interaction may constitute the basis for a local immunological barrier and may be involved in the protection of the fetus against maternal immune rejection.

Animals↗
PubMedDate not supplied

Differences in polyamine metabolism between carcinomatous and uninvolved human breast tissues.

The polyamine biosynthetic enzymes ODC and SAMDC show higher activity in carcinomatous human breast tissue than in uninvolved tissue of the same breast; the interconversion enzyme PAO shows significantly lower activity in carcinomatous than uninvolved tissue. The polyamine metabolism in carcinomatous human breast tissue thus appears to differ from that in uninvolved tissue. Intracellular polyamine concentrations, particularly spermine, are high in carcinomatous tissue. This increase and that of the biosynthetic enzymes suggest that a higher polyamine concentration is needed for carcinomatous cell growth. If this is the case, the lower PAO activity in carcinomatous tissue may be explained as a mechanism that conserves the high intracellular polyamine concentration.

Adenosylmethionine Decarboxylase↗
PubMed2005

Activity of peroxisomal enzymes, and levels of polyamines in LPA-transgenic mice on two different diets.

BACKGROUND: In man, elevated levels of plasma plipoprotein (a) (Lp(a)) is a cardiovascular risk factor, and oxidized phospholipids are believed to play a role as modulators of inflammatory processes such as atherosclerosis. Polyamines are potent antioxidants and anti-inflammatory agents. It was therefore of interest to examine polyamines and their metabolism in LPA transgenic mice. Concentration of the polyamines putrescine, spermidine and spermine as well as the activity of peroxisomal polyamine oxidase and two other peroxisomal enzymes, acyl-CoA oxidase and catalase were measured. The mice were fed either a standard diet or a diet high in fat and cholesterol (HFHC). Some of the mice in each feeding group were in addition given aminoguanidine (AG), a specific inhibitor of diamine oxidase, which catalyses degradation of putrescine, and also inhibits non-enzymatic glycosylation of protein which is implicated in the aetiology of atherosclerosis in diabetic patients. Non-transgenic mice were used as controls. RESULTS: Intestinal peroxisomal polyamine oxidase activity was significantly higher in LPA transgenic mice than in the non-transgenic mice, while intestinal peroxisomal catalase activity was significantly lower. Hepatic beta-oxidation increased in Lp(a) transgenic mice fed the HFHC diet, but not in those on standard diet. Hepatic spermidine concentration was increased in all mice fed the HFHC diet compared to those fed a standard diet, while spermine concentration was decreased. With exception of the group fed only standard diet, transgenic mice showed a lower degree of hepatic steatosis than non-transgenic mice. AG had no significant effect on hepatic steatosis. CONCLUSION: The present results indicate a connection between peroxisomal enzyme activity and the presence of the human LPA gene in the murine genome. The effect may be a result of changes in oxidative processes in lipid metabolism rather than resulting from a direct effect of the LPA construct on the peroximal gene expression.

Acyl-CoA Oxidase↗
PubMedDate not supplied

Altered growth and polyamine catabolism following exposure of the chocolate spot pathogen Botrytis fabae to the essential oil of Ocimum basilicum.

Biomass of the fungal pathogen Botrytis fabae in liquid culture amended with two chemotypes of the essential oil of basil, Ocimum basilicum, was reduced significantly at concentrations of 50 ppm or less. The methyl chavicol chemotype oil increased the activity of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), but polyamine concentrations were not significantly altered. In contrast, the linalol chemotype oil decreased AdoMetDC activity in B. fabae, although again polyamine concentrations were not altered significantly. However activities of the polyamine catabolic enzymes diamine oxidase (DAO) and polyamine oxidase (PAO) were increased significantly in B. fabae grown in the presence of the essential oil of the two chemotypes. It is suggested that the elevated activities of DAO and PAO may be responsible, in part, for the antifungal effects of the basil oil, possibly via the generation of hydrogen peroxide and the subsequent triggering of programmed cell death.

Adenosylmethionine Decarboxylase↗
PubMed2000

Alterations in polyamine catabolic enzymes in human breast cancer tissue.

High concentrations of acetyl polyamines have been observed in human breast cancer compared with the equivalent normal tissue, however, no explanation as to the reason for the increases has been proposed. In this study, we show that changes in the enzymes responsible for the breakdown of acetyl polyamines occur in breast cancer tissue. Spermidine/spermine N1-acetyltransferase, the first and rate-limiting enzyme in polyamine catabolism, is increased in the tumor tissue whereas polyamine oxidase (PAO) is decreased. The changes in PAO correlate with prognostic factors, and activity decreases as the size and histological grade of tumors increase. The metabolism of polyamines by PAO generates locally high concentrations of hydrogen peroxide, a known inducer of apoptosis; thus, low PAO activity may contribute to the low level of apoptosis seen in tumor cells. Therefore, drugs that induce PAO activity may be a novel means of attacking tumor cells.

Acetylation↗
PubMedDate not supplied

Inhibition of the growth of U-251 human glioblastoma in nude mice by polyamine deprivation.

An almost complete prevention of tumor growth was achieved in U-251 human glioblastoma xenografted nude mice, by partial decontamination of the gastrointestinal tract and feeding of a polyamine-free diet containing inhibitors of ornithine decarboxylase (DFMO) and of polyamine oxidase (MDL 72527). After one week of polyamine deprivation, spermidine concentrations were lowered, and spermine levels were increased in all tissues. In contrast, putrescine concentrations were only reduced in tumor and in brain. Erythrocyte polyamine determinations revealed differences similar to those observed in tissues: spermidine concentration was lowered by 50% and spermine level was 3-fold increased. If this or related treatments should become of therapeutic importance in the future, then the determination of erythrocyte polyamine levels might be of diagnostic value.

Animals↗
PubMedDate not supplied

Putrescine, polyamines, and N1-acetylpolyamine levels in retina, visual cortex and cerebellum of free-running mice kept under continuous light or darkness.

Putrescine, spermidine and spermine levels were detected in the retina, visual cortex, cerebellum and parietal cortex of CD1 mice exposed to 36h continuous light or darkness. Retinal putrescine and polyamine concentrations were found to be highest in dark-adapted mice, and the stimulation of dark-adapted retina with flicker illumination was also accompanied by a significant decrease in putrescine, spermidine and spermine levels. In visual cortex as well as in cerebellum spermidine and spermine contents were higher in dark-adapted mice in comparison to light-exposed animals, while in parietal cortex no significant change was found neither in spermidine nor spermine levels. In the brain areas studied flicker illumination produced no significant decreases in putrescine and polyamine contents. The total polyamines expressed as putrescine equivalents were noticeably decreased in retina, visual cortex and cerebellum of light-adapted mice. In the retina spermine/spermidine molar ratio was significantly higher than in dark-adapted mice. The administration of N1, N2-bis-(2,3-butadienyl)-1,4-butanediamine (MDL 72527) produced a strong decrease of retinal putrescine and spermidine concentrations in both dark-adapted and light-exposed mice, and in the retina of mice exposed to continuous light a significant decrease in the spermine level was also observed. According to the influence on polyamine reutilization, after the irreversible inhibition of polyamine oxidase by MDL 72527, in the retina N1-acetylspermidine and N1-acetylspermine accumulation was highest in light-adapted mice. On the contrary in visual cortex, cerebellum and parietal cortex the MDL 72527 administration produced a more marked decrease of putrescine and spermidine contents in mice kept in continuous darkness.

Animals↗