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At least 271 records · Page 15Linked to original sources
PubMed1990

Regulation of polyamine transport in Chinese hamster ovary cells.

Control Chinese hamster ovary (CHO) cells and mutant CHO cells lacking ornithine decarboxylase activity (CHODC-) were used to study the regulation of polyamine uptake. It was found that the transport system responsible for this uptake was regulated by intracellular polyamine levels and that this regulation was responsible for the maintenance of physiological intracellular levels under extreme conditions such as polyamine deprivation or exposure to exogenous polyamines. Polyamine transport activity was enhanced by decreases in polyamine content produced either by inhibition of ornithine decarboxylase with alpha-difluoromethylornithine in CHO cells or via polyamine starvation of CHODC- cells. The provision of exogenous polyamines resulted in rapid and large increases in intracellular polyamine content followed by decreased polyamine transport activity. Soon after this decrease in uptake activity, intracellular polyamine levels then fell to near control values. Cells grown in the presence of exogenous polyamines maintained intracellular polyamine levels at values similar to those of control cells. Protein synthesis was necessary for the increase in transport in response to polyamine depletion, but appeared to play no role in decreasing polyamine transport. Bis(ethyl) polyamine analogues mimicked polyamines in the regulation of polyamine transport but this process was relatively insensitive to regulation by methylglyoxal bis(guanylhydrazone), a spermidine analogue known to enter cells via this transport system and to accumulate to very high levels.

Animals↗
PubMed2001

Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications.

Polyamines are aliphatic cations with multiple functions and are essential for life. Cellular polyamine levels are regulated by multiple pathways such as synthesis from amino acid precursors, cellular uptake mechanisms that salvage polyamines from diet and intestinal microorganisms, as well as stepwise degradation and efflux. Investigations using polyamine biosynthetic inhibitors indicate that alterations in cellular polyamine levels modulate normal and cancer cell growth. Studies using transgenic mice overexpressing polyamine biosynthetic enzymes support a role of polyamines in carcinogenesis. Many, if not all, signal transduction pathways intersect with polyamine biosynthetic pathways and the regulation of intracellular polyamine levels. Direct binding of polyamines to DNA and their ability to modulate DNA-protein interactions appear to be important in the molecular mechanisms of polyamine action in cell proliferation. Consistent with the role of polyamines as facilitators of cell growth, several studies have shown their ability to protect cells from apoptosis. However, polyamines also have a role in facilitating cell death. The basis of these diverse cellular responses is currently not known. Cell death response might be partly mediated by the production of hydrogen peroxide during polyamine catabolism. In addition, the ability of polyamines to alter DNA-protein and protein-protein interactions might be disruptive to cellular functions, when abnormally high levels are accumulated due to defects in polyamine catabolic or efflux pathways. A large body of data indicates that polyamine pathway can be a molecular target for therapeutic intervention in several types cancers. Inhibitors of biosynthesis, polyamine analogues as well as oligonucleotide/polyamine analogue combinations are promising drug candidates for chemoprevention and/or treatment of cancer.

Animals↗
PubMed1989

Properties and physiological function of the polyamine transport system.

Polyamine transport was examined in Chinese hamster ovary (CHO) cells because of the unique potential these cells hold for utilizing genetic approaches to study the mechanisms of polyamine transport, its regulation, and its function. Parental (control) CHO cells were shown to contain a polyamine transport system with characteristics consistent with polyamine-uptake properties described in other cell types. Polyamines appear to cross the plasma membrane via an energy-requiring transport system specific for putrescine, spermidine, spermine, and their analogues. A mutant line, CHOMG, selected for resistance to the toxicity of methylglyoxal bis(guanylhydrazone), was shown to lack a functional polyamine transport system. CHOMG cells provided the negative controls necessary to examine the role of polyamine transport in maintenance of intracellular polyamine levels and in the regulation of the polyamine metabolic enzymes. It was found that the repression of ornithine decarboxylase activity by polyamines and the induction of spermidine/spermine-N1 acetyltransferase by polyamine analogues including bis(ethyl)spermine derivatives required the presence of a functional polyamine transport system. The CHO-CHOMG model was also shown to provide a means for establishing the importance of the polyamine transport system in the toxicity of polyamine analogues. The inability of alpha-difluoromethylornithine-treated CHOMG cells to utilize extracellular polyamines to replenish depleted intracellular polyamine levels suggested a means by which polyamine transport-positive cells may be identified. Such a selection procedure will permit the use of CHOMG cells in the isolation of genes encoding proteins involved in polyamine transport.

Animals↗
PubMed2005

Molecular mechanisms of polyamine analogs in cancer cells.

The natural polyamines are aliphatic cations with multiple functions and are essential for cell growth. Soon after the critical requirement of polyamines for cell proliferation was recognized, the metabolism of polyamines was pursued as a target for antineoplastic therapy. Initially, much attention was focused on the development of inhibitors of polyamine biosynthesis as a means to inhibit tumor growth. The best-characterized inhibitor is alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. While compensatory mechanisms in polyamine metabolism reduce the effectiveness of DFMO as a single chemotherapeutic agent, it is currently undergoing extensive testing and clinical trials for chemoprevention and other diseases. There has been increasing interest over the last two decades in the cytotoxic response to agents that target the regulation of polyamine metabolism rather than directly inhibiting the metabolic enzymes in tumor cells. This interest resulted in the development of a number of polyamine analogs that exhibit effective cytotoxicity against tumor growth in preclinical models. The analogs enter cells through a selective polyamine transport system and can be either polyamine antimetabolites that deplete the intracellular polyamines or polyamine mimetics that displace the natural polyamines from binding sites, but do not substitute in terms of growth-promoting function. Synthesis of the first generation of symmetrically substituted bis(alkyl)polyamine analogs in the mid-1980s was based on the theory that polyamines may utilize feedback mechanisms to auto-regulate their synthesis. In the 1990s, unsymmetrically substituted bis(alkyl) polyamine analogs were developed. These compounds display structure-dependent and cell type-specific cellular effects and regulation on polyamine metabolism. More recently, a novel class of analogs has been synthesized, which include conformationally restricted, cyclic and long-chain oligoamine analogs. The development and use of these analogs have provided valuable information for understanding the molecular mechanisms of targeting the polyamine pathway as a means of cancer therapy.

Animals↗
PubMed2003

The role of polyamine catabolism in anti-tumour drug response.

Interest in polyamine catabolism has increased since it has been directly associated with the cytotoxic response of multiple tumour types to exposure to specific anti-tumour polyamine analogues. Human polyamine catabolism was considered to be a two-step pathway regulated by the rate-limiting enzyme spermidine/spermine N(1)-acetyltransferase (SSAT) that provides substrate for an acetylpolyamine oxidase (APAO). Further, the super-induction of SSAT by several anti-tumour polyamine analogues has been implicated in the cytotoxic response of specific solid-tumour phenotypes to these agents. This high induction of SSAT has been correlated with cellular response to the anti-tumour polyamine analogues in several systems and considerable progress has been made in understanding the molecular mechanisms that regulate the analogue-induced expression of SSAT. A polyamine response element has been identified and the transacting transcription factors that bind and stimulate transcription of SSAT have been cloned and characterized. The link between SSAT activity and cellular toxicity is thought to be based on the production of H(2)O(2) by the activity of the constitutive APAO that uses the SSAT-produced acetylated polyamines. The high induction of SSAT and the subsequent activity of APAO are linked to the cytotoxic response of some tumour cell types to specific polyamine analogues. However, we have recently cloned a variably spliced human polyamine oxidase (PAOh1) that is inducible by specific polyamine analogues, efficiently uses unacetylated spermine as a substrate, and also produces toxic H(2)O(2) as a product. The results of studies with PAOh1 suggest that it is an additional enzyme in polyamine catabolism that has the potential to significantly contribute to polyamine homoeostasis and drug response. Most importantly, PAOh1 is induced by specific polyamine analogues in a tumour-phenotype-specific manner in cell lines representative of the major forms of solid tumours, including lung, breast, colon and prostate. The sensitivity to these anti-tumour polyamine analogues can be significantly reduced if the tumour cells are co-treated with 250 microM of the polyamine oxidase inhibitor N (1), N (4)-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72,527), suggesting that the H(2)O(2) produced by PAOh1 does in fact play a direct role in the observed cytotoxicity. These results strongly implicate PAOh1 as a new target that, in combination with SSAT, may be exploited for therapeutic advantage. The current understanding of the role and regulation of these two important polyamine catabolic enzymes are discussed.

Acetyltransferases↗
PubMed1985

The value of urinary polyamine assay in stomach cancer. Comparison with serum carcinoembryonic antigen.

The authors recently established a new simple enzymatic assay method for total urinary polyamines (Cancer Res 1983; 43:2263-2367). In order to assess the clinical usefulness of measuring total urinary polyamines for the detection of cancer, this method has been applied to the assay of polyamines in the urine of 45 patients with stomach cancer who were classified as to clinical stage. In addition, the value of serum carcinoembryonic antigen (CEA) in the same individual patients was measured for comparison. Percentage of patients with elevated levels of total urinary polyamines increased with International Union Against Cancer (UICC) clinical stage, and was 40.0% (6/15), 50% (3/6), 72.7% (8/11), and 84.6% (11/13) for Stage I, II, III and IV stomach cancer patients, respectively. In 32 patients with stomach cancer of potentially operable Stage I, II, and III, elevated levels of total urinary polyamines were found in 17 patients and elevated levels of serum CEA were found in 5 patients. In 13 patients with inoperable stage IV stomach cancer, elevated levels of total urinary polyamines were found in 11 patients and elevated levels of serum CEA were found in 5 patients. Statistical differences in the detection rate were found between the two markers in these two groups of patients. The combination of these two markers did not increase the detection rate of stomach cancer significantly. The data indicate that the determination of total urinary polyamines by the new assay is clinically useful as a potential marker for the detection of advanced stages of stomach cancer and may be more useful than that of serum CEA. Furthermore, this study demonstrates the relationship between urinary polyamine levels and tumor regression and also the prognostic significance of polyamine determination in stomach cancer patients. In 6 of 13 patients who showed elevated levels of urinary polyamines before surgery, polyamine levels fell to within the normal range after successful surgical removal of tumor. In general, each polyamine level decreased significantly following surgery by paired Student's t test analysis. All of the five Stage IV patients with polyamine levels greater than 4.0 mumol/kg/24 hour died in less than 3 months whereas five of eight Stage IV patients with polyamine levels less than or equal to 4.0 mumol/kg/24 hour survived 10 to 20 months. Statistical differences in survival were observed between Stage IV patients with polyamine levels greater than 4.0 mumol/kg/24 hour and those with polyamine levels less than or equal to 4.0 mumol/kg/24 hour.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinoembryonic Antigen↗
PubMed1992

Uptake and cytotoxicity of novel nitroimidazole-polyamine conjugates in Ehrlich ascites tumour cells.

A number of tumour cells, including Ehrlich ascites tumour cells (EATC), possess a polyamine uptake system which selectively accumulates endogenous polyamines and structurally related compounds by an active energy dependent system(s). We suggest that it may be possible to utilize this uptake system to target certain cytotoxic agents to those tumour cells possessing this system. In an initial attempt to determine the feasibility of this suggestion, we have synthesized a series of 2- and 5-nitroimidazoles linked to polyamines and determined their ability to utilize the polyamine uptake system. Within the limited series of compounds synthesized, 2-nitroimidazole-polyamine conjugates were more potent inhibitors of spermidine uptake into EATC than the 5-nitroimidazole conjugates. It has been assumed partly based on the competitive nature of this inhibition, that the ability of these compounds to inhibit spermidine uptake is also a measure of their ability to be accumulated by EATC. A greater than 700-fold variation was observed in the ability of different analogues to inhibit spermidine uptake. The most potent inhibitors retained certain structural characteristics similar to those of spermidine. Those compounds linked to polyamines were much more potent inhibitors of polyamine uptake than the parent nitroimidazoles i.e. metronidazole and misonidazole. The toxicity of the parent compounds and their polyamine conjugates in control and polyamine-depleted EATC was assessed by measuring inhibition of tritiated thymidine incorporation. Polyamine depletion, by prior exposure to difluoromethylornithine, results in a compensatory increase in the uptake of polyamines and related structures which may result in an increase in toxicity. Whilst many of the novel conjugates showed only little or moderate toxicity to control cells, the toxicity of several of the conjugates but not the parent nitroimidazoles increased in the polyamine-depleted cells. A clear distinction was also observed between the ability to inhibit spermidine uptake (and hence affinity for the uptake system) and toxicity, e.g. compound 430, a dinitroimidazole-polyamine conjugate, was the best inhibitor of spermidine uptake studied but showed no toxicity. These results support the hypothesis that linking polyamines to nitroimidazoles facilitates the entry of the latter into cells, such as EATC, which possess the polyamine uptake system and may therefore have therapeutic application in the delivery of polyamine-linked cytotoxics to certain tumours.

Animals↗
PubMed1994

Characterization of polyamine transport in rat aortic smooth muscle cells.

Increased arterial wall polyamine content has been linked to intimal hyperplasia (IH) formation. Intracellular polyamine content may be regulated by a polyamine transmembrane transport mechanism, but the existence of such a system has not been demonstrated in systemic arterial smooth muscle cells. This study characterizes polyamine transport as found in rat aortic smooth muscle cells. Smooth muscle cells were isolated and cultured from Sprague-Dawley rat aortas. Polyamine transport was determined by adding [14C]-polyamines to the medium, calculating transport kinetic parameters, Vmax and Km. Competition studies with unlabeled polyamines and uptake in the presence of paraquat, a polyamine transport inhibitor, were done to test the specificity of the uptake system. We identified polyamine transporters in aortic smooth muscle cells which were temperature, concentration, and time dependent. Kinetic studies revealed that spermidine and spermine had greater affinity for the transporter(s) than putrescine (Km = 0.3, 0.3, and 3.7 microM respectively; P = 0.0001) while maximum uptake velocity was similar for all polyamines (26.6-31.0 pmole/mg protein/min). Inhibition of de novo polyamine synthesis upregulated polyamine transport 2.8-3.8 times (P = 0.0001) while transporter affinity (as reflected by Km) remained unchanged. Competition studies and paraquat treatment indicated the presence of two polyamine transporters: one shared by all polyamines, the other specific for spermine and spermidine. These data indicate that transmembrane polyamine transport occurs in arterial smooth muscle cells. Upregulation of this system may represent one control mechanism for IH development.

Animals↗
PubMed1991

Polyamine--DNA nexus: structural ramifications and biological implications.

Polyamines at physiological concentration can condense DNA, chromatin and promote B to Z DNA transitions. These properties of polyamines are crucial to the molecular organization and functional control of DNA and thus have very significant implications in the control of cellular functions. The structure of polyamines plays an important role in the binding of DNA and chromatin and it is not merely the charge, but a specific chain length of methylene (-CH2) groups that is required. Acetylation of polyamines seems to be an important mode of regulating polyamine-chromatin interaction. Purified histone acetyltransferase also possesses polyamine acetylation activity, thus histones and polyamine acetylation may occur in tandem to alter the structure/function of the nucleosome thereby regulating DNA replication and transcription. Acetylation as a means to diminish the number of charges on polyamine molecules serves as an ordered mechanism to control DNA replication and transcription in vivo. The results on the involvement of polyamines and their analogs in condensation of DNA and B to Z DNA transition correlate well with the conclusions drawn from experiments designed to observe the in vivo effects of polyamines and their analogs on the growth of prokaryotic and eukaryotic cells. For example, any change in the hydrogen bonding capacity of polyamines leads to a marked reduction in protein synthesis and the growth rate of polyamine depleted cells. A minimal level of polyamines is required for cells to move from G1 through S phase and these amines are directly involved in the DNA synthetic phase of the cell cycle. A nexus between polyamines and nucleic acids appears crucial to the cellular function(s) of polyamines.

Acetylation↗
PubMed1994

Role of ATP and sodium in polyamine transport in bovine pulmonary artery smooth cells.

Increased polyamine transport may be a key mechanism driving elevations in lung cell polyamine content necessary for the development of chronic hypoxic pulmonary hypertension. Bovine pulmonary artery smooth muscle cells (PASMCs) in culture exhibit two carriers for polyamines, a non-selective one shared by the three polyamines, putrescine (PUT), spermidine (SPD), and spermine (SPM), and another that is selective for SPD and SPM. Hypoxia appears to up-regulate both carriers. In this study, we examined the role of ATP and the Na+ gradient in regulating polyamine transport in control PASMCs and in PASMCs with polyamine transport augmented by culture under hypoxic conditions (Po2: 15-30 torr). Inhibition of ATP synthesis with dinitrophenol+iodoacetate profoundly reduced polyamine uptake in both control and hypoxic PASMCs. Putrescine uptake was somewhat more sensitive to iso-osmotic replacement of extracellular Na+ with choline chloride or sucrose than were SPD or SPM in both hypoxic and standard cells, but under no conditions did Na+ replacement substantially alter polyamine uptake. Treatment of PASMCs with ouabain, a Na(+)-K+ ATPase inhibitor, or with gramicidin, a Na+ ionophore, minimally attenuated polyamine transport, whereas the Na+/K+ ionophore monensin increased polyamine uptake in standard, but not in hypoxic, cells. In general, the reduction in the extracellular Na+ content or ionophore-induced increases in Na+ permeability had a greater suppressive effect on polyamine transport in hypoxic cells than in standard cells, suggestive of the induction of Na(+)-dependent polyamine carriers by hypoxia. These observations indicate that the activities of the two putative polyamine transport pathways in standard PASMCs, as well as their up-regulation by hypoxia, require ATP synthesis. In addition, it appears that polyamine transport in PASMCs is composed of two components: one a prominent sodium-independent transporter and the other a relatively minor component that is sodium dependent. The latter may be activated by hypoxic exposure in combination with the induction of new polyamine carriers.

Adenosine Triphosphate↗