Polyamines and cancer: Minireview article

Summary. 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.     

Molecular Genetic Analyses of Plant Polyamines

Polyamines are small, positively charged aliphatic amines that play a variety of roles in plant physiology. Putrescine, spermidine, and spermine are usually what are collectively meant by the term polyamines, although plants also have a variety of other related compounds and secondary product conjugates to polyamines. Organisms synthesize putrescine, spermidine, and spermine by pathways leading from ornithine, arginine, and SAM, with three of the important enzymes being amino acid decarboxylases. There has been recent progress in understanding plant polyamines, both their function and the regulation of their synthesis, as a result of molecular genetic investigations. The cDNAs for many of the key enzymes have been cloned and se-quenced, and studies on regulation of the enzymes have begun. Mutational and transgenic approaches are being used to perturb the pathway. Some of the phenotypes observed suggest interactions between polyamines and either ethylene or cytokinin, consistent with some of the correlations observed many years previously by polyamine physiologists. These studies, while still in their early stages, should improve our understanding of polyamine synthesis, but difficult problems remain to be solved before we can answer the question: What are the biological functions and associated mechanisms of action of polyamines?     

Spermine and spermidine mediate protection against oxidative damage caused by hydrogen peroxide

Summary. The polyamines spermidine and spermine have been hypothesized to possess different functions in the protection of DNA from reactive oxygen species. The growth and survival of mouse fibroblasts unable to synthesize spermine were compared to their normal counterparts in their native and polyamine-depleted states in response to oxidative stress. The results of these studies suggest that when present at normal or supraphysiological concentrations, either spermidine or spermine can protect cells from reactive oxygen species. However, when polyamine pools are pharmacologically manipulated to produce cells with low levels of predominately spermine or spermidine, spermine appears to be more effective. Importantly, when cells are depleted of both glutathione and endogenous polyamines, they exhibit increased sensitivity to hydrogen peroxide as compared to glutathione depletion alone, suggesting that polyamines not only play a role in protecting cells from oxidative stress but this role is distinct from that played by glutathione.     

Polyamines: mysterious modulators of cellular functions

In recent years the functions of polyamines (putrescine, spermidine, and spermine) have been studied at the molecular level. Polyamines can modulate the functions of RNA, DNA, nucleotide triphosphates, proteins, and other acidic substances. A major part of the cellular functions of polyamines can be explained through a structural change of RNA which occurs at physiological concentrations of Mg(2+) and K(+) because most polyamines exist in a polyamine-RNA complex within cells. Polyamines were found to modulate protein synthesis at several different levels including stimulation of special kinds of protein synthesis, stimulation of the assembly of 30 S ribosomal subunits and stimulation of Ile-tRNA formation. Effects of polyamines on ion channels have also been reported and are gradually being clarified at the molecular level.     

Inhibitors of polyamine biosynthesis affect the expression of genes encoding cytoskeletal proteins.

The polyamines are ubiquitous components of mammalian cells. Those compounds have been postulated to play an important role in different cellular functions including the reorganization of cytoskeleton associated with the cell cycle. In the studies reported here, it was found that inhibitors of polyamine biosynthesis, methylglyoxal-bis[quanylhydrazone] (MGBG) and difluoromethylornithine (DFMO), prevent mitogen-induced accumulation of mRNAs encoding major cytoskeletal components, beta-actin and alpha-tubulin, in mouse splenocytes. These findings suggest mechanisms through which polyamines may exert their effects on the cytoskeleton integrity.     

Signal transduction pathways linking polyamines to apoptosis

Summary. Polyamines are important multifunctional cellular components and are classically considered as mediators of cell growth and division. Recently polyamines have been also implicated in cell death. Now it appears that polyamines are bivalent regulators of cellular functions, promoting proliferation or cell death depending on the cell type and on environmental signals. This review draws a picture about the role of polyamines in signalling pathways related to apoptotic cell death and the proposed molecular targets of these polycations at the level of the apoptotic cascade. Solid evidence indicates that polyamines may affect the mitochondrial and postmitochondrial phases of apoptosis, by modulating cytochrome c release from mitochondria and activation of caspases. Recently, polyamines have been also implicated in the regulation of the premitochondrial phase of apoptosis, during which upstream apoptotic signal transduction pathways are activated. The studies reviewed here suggest that polyamines may participate in loops involving interaction with signal transduction pathways and activation/expression of proteins that may control cell death or cell growth.     

Evidence of different G-quadruplex DNA binding with biogenic polyamines probed by electrospray ionization-quadrupole time of flight mass spectrometry,circular dichroism and atomic force microscopy

The binding properties of five G-quadruplex oligonucleotides (humtel24, k-ras32, c-myc22, c-kit1 and c-kit2) with polyamines have been investigated by electrospray ionization-quadrupole time of flight mass spectrometry, circular dichroism, melting temperature, atomic force microscopy (AFM) and molecular simulation. The MS results demonstrated that the polyamines and G-quadruplex DNA can form complexes with high affinity, and one molecule of G-quadruplex DNA can combine several molecules (1–5) of polyamines. The binding affinities of the polyamines to DNA were in the order of spermine > spermidine > putrescine. After binding with polyamines, the conformations of the G-quadruplex DNA were significantly changed, and spermine can induce the configurations of k-ras32 and c-kit1 to deviate from their G-quadruplex structures at high concentrations. In the presence of K⁺, the conformations of G-quadruplex DNA were stabilized, while polyamines can also induced alterations of their configurations. Melting temperature experiments suggested that the T_m of the DNA–polyamine complexes obviously increased both in the absence and presence of K⁺. The AFM results indicated that polyamines can induce aggregation of G-quadruplex DNA. Above results illustrated that the polyamines bound with the phosphate backbone and the base-pairs of G-quadruplex structures. Combining with the molecular simulation, the binding mode of the G-quadruplex DNA and polyamines were discussed. The results obtained would be beneficial for understanding the biological and physiological functions of polyamines and provide useful information for development of antitumor drugs.     

Selective regulation of polyamine metabolism with methylated polyamine analogues

Polyamine metabolism is intimately linked to the physiological state of the cell. Low polyamines levels promote growth cessation, while increased concentrations are often associated with rapid proliferation or cancer. Delicately balanced biosynthesis, catabolism, uptake and excretion are very important for maintaining the intracellular polyamine homeostasis, and deregulated polyamine metabolism is associated with imbalanced metabolic red/ox state. Although many cellular targets of polyamines have been described, the precise molecular mechanisms in these interactions are largely unknown. Polyamines are readily interconvertible which complicate studies on the functions of the individual polyamines. Thus, non-metabolizable polyamine analogues, like carbon-methylated analogues, are needed to circumvent that problem. This review focuses on methylated putrescine, spermidine and spermine analogues in which at least one hydrogen atom attached to polyamine carbon backbone has been replaced by a methyl group. These analogues allow the regulation of both metabolic and catabolic fates of the parent molecule. Substituting the natural polyamines with methylated analogue(s) offers means to study either the functions of an individual polyamine or the effects of altered polyamine metabolism on cell physiology. In general, gem-dimethylated analogues are considered to be non-metabolizable by polyamine catabolizing enzymes spermidine/spermine-N ¹-acetyltransferase and acetylpolyamine oxidase and they support short-term cellular proliferation in many experimental models. Monomethylation renders the analogues chiral, offering some advantage over gem-dimethylated analogues in the specific regulation of polyamine metabolism. Thus, methylated polyamine analogues are practical tools to meet existing biological challenges in solving the physiological functions of polyamines.     

Cellular and subcellular localization of polyamines cytochemical methods providing new clues to polyamine function in normal and neoplastic cells

Summary Studies on the cellular and subcellular localization of polyamines have previously been hampered by the rapid redistribution of these organic cations during cell fractionation. Cytochemical methods selectively localizing polyamines would, hence, be important for our understanding of where polyamines are stored and where they work. With the aid of chemical characterizations of tissue extracts, biosynthesis experiments and cytochemical model experiments we show that the cytochemical formaldehyde-fluorescamine (FF) technique selectively detects the polyamines spermine and spermidine. Results obtained with the FF method concur with previous chemical observations by showing that growing and neoplastic cell populations are rich in cytochemically detectable polyamines. The FF method also localizes polyamines to certain normal secretory cell systems, including pancreatic exocrine and endocrine (insulin) cells, cells and secretion products in the ventral prostate, pituitary growth hormone cells and neurosecretory nerve endings and leucocytes. In most cell systems studied, polyamines appear to be most concentrated in cytoplasmic structures. However, in HeLa cell mitotic chromosomes and in frog red cell nuclei most polyamines seem to be associated with chromatin. These observations raise important questions concerning both extra- and intracellular functions of polyamines.     

Management of polyamine pools and the regulation of ornithine decarboxylase

The management of polyamine synthesis and polyamine pools differs fundamentally from that of most other small molecular-weight endproducts. The polyamines are vital to growth and important cellular functions, but they are toxic in excess. I argue here that their multivalent cationic character, leading to binding to cell constituents, precludes fluent feedback inhibition of synthesis. This has led to the development of elaborate alternative regulatory mechanisms controlling ornithine decarboxylase, the key initial enzyme of the pathway. Poorly regulated polyamine synthesis and the toxicity of polyamines impose upon cells a need to control uptake and to dispose of excess polyamines. Recent data on polyamine transport suggest unorthodox mechanisms of accomplishing these functions.     

生物体内多胺对蛋白质影响的研究进展

多胺是普遍存在于生物体中的一种脂肪族阳离子胺。多胺通过离子键和氢键的形式与生物大分子结合,调节生物大分子的生物学活性,调控细胞的生长和发育。多胺对核酸的作用一直是关注热点,而针对蛋白质的影响目前研究较少。本文主要针对多胺调控代谢相关酶、通道蛋白质和其他功能性蛋白质以及相关规律和机制进行综述,并从蛋白质结构和功能角度探讨了多胺与蛋白质之间的相互作用关系,同时总结了多胺与蛋白质相互作用研究在疾病治疗中的应用前景和面临的问题。     

多胺与植物衰老关系研究进展

多胺作为生理活性物质与植物衰老关系密切。本文综述了近十多年来多胺对衰老的调控作用,从调节细胞膜的理化性质、生物大分子合成作用以及多胺与乙烯的关系等方面阐述了多胺延缓衰老的机制,比较了多胺和影响衰老的植物激素在信号转导过程中的作用。     

多胺与植物衰老关系研究进展

多胺作为生理活性物质与植物衰老关系密切。本文综述了近十年来多胺对衰老的调控作用,从调节细胞膜的理化性质,生物大分子合成作用以及多胺与乙烯的关系等方面阐述了多胺延缓衰老的机制,比较了多胺和影响衰老的植物激素在信号转导过程中的作用。     

植物多胺代谢途径研究进展

多胺是一类小分子生物活性物质,广泛存在于生物体内,与植物的生长发育、衰老及抗逆性都有着密切的联系。目前,在植物中的多胺合成途径已经基本揭示,其生理作用在分子水平上逐步得到阐明。对多胺合成突变体和各种转基因植物的研究也使得人们更深入地了解了多胺以及其合成代谢相关酶在植物生长发育等生理过程中的重要作用。以下概述了植物多胺代谢途径,重点综述了代谢途径中各基因的功能及遗传操作的最新进展,并对将来的研究方向尤其是相关基因在植物抗逆境 (包括生物和非生物逆境) 基因工程方面的应用作了讨论。     

Polyamines are unevenly distributed within the rat and rabbit kidney

Summary. Aliphatic polyamines have generally been measured on the whole kidney. Since the kidney is composed of a variety of cells, whole organ data are of limited value for the interpretation of the functions of the polyamines. The aim of this study was to establish the distribution pattern of putrescine, spermidine and spermine within the kidneys of male and female rats and rabbits. It is shown that the polyamines are unevenly distributed along the cortico-papillary axis. Each amine exhibited its own distinct distribution pattern. The polyamines are predominantly located in the cortex. Putrescine levels increased gradually from the cortex to the papillary tip in rabbits, whereas, in rats, fluctuations in putrescine level were marked. In the six zones of the rabbit kidney studied, spermidine and spermine concentrations were markedly higher in females than in males. This difference was less marked in rats. Received April 1, 1999, Accepted May 17, 1999     

Polyamines and abiotic stress: recent advances

Summary. In this review we will concentrate in the results published the last years regarding the involvement of polyamines in the plant responses to abiotic stresses, most remarkably on salt and drought stress. We will also turn to other types of abiotic stresses, less studied in relation to polyamine metabolism, such as mineral deficiencies, chilling, wounding, heavy metals, UV, ozone and paraquat, where polyamine metabolism is also modified. There is a great amount of data demonstrating that under many types of abiotic stresses, an accumulation of the three main polyamines putrescine, spermidine and spermine does occur. However, there are still many doubts concerning the role that polyamines play in stress tolerance. Several environmental challenges (osmotic stress, salinity, ozone, UV) are shown to induce ADC activity more than ODC. The rise in Put is mainly attributed to the increase in ADC activity as a consequence of the activation of ADC genes and their mRNA levels. On the other hand, free radicals are now accepted as important mediators of tissue injury and cell death. The polycationic nature of polyamines, positively charged at physiological pH, has attracted the attention of researchers and has led to the hypothesis that polyamines could affect physiological systems by binding to anionic sites, such as those associated with nucleic acids and membrane phospholipids. These amines, involved with the control of numerous cellular functions, including free radical scavenger and antioxidant activity, have been found to confer protection from abiotic stresses but their mode of action is not fully understood yet. In this review, we will also summarize information about the involvement of polyamines as antioxidants against the potential abiotic stress-derived oxidative damage. Authors’ address: Dr. María Patricia Benavides, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, Buenos Aires 1113, Argentina     

Genetic approaches to the cellular functions of polyamines in mammals.

The polyamines putrescine, spermidine and spermine are organic cations shown to participate in a bewildering number of cellular reactions, yet their exact functions in intermediary metabolism and specific interactions with cellular components remain largely elusive. Pharmacological interventions have demonstrated convincingly that a steady supply of these compounds is a prerequisite for cell proliferation to occur. The last decade has witnessed the appearance of a substantial number of studies, in which genetic engineering of polyamine metabolism in transgenic rodents has been employed to unravel their cellular functions. Transgenic activation of polyamine biosynthesis through an overexpression of their biosynthetic enzymes has assigned specific roles for these compounds in spermatogenesis, skin physiology, promotion of tumorigenesis and organ hypertrophy as well as neuronal protection. Transgenic activation of polyamine catabolism not only profoundly disturbs polyamine homeostasis in most tissues, but also creates a complex phenotype affecting skin, female fertility, fat depots, pancreatic integrity and regenerative growth. Transgenic expression of ornithine decarboxylase antizyme has suggested that this unique protein may act as a general tumor suppressor. Homozygous deficiency of the key biosynthetic enzymes of the polyamines, ornithine and S-adenosylmethionine decarboxylase, as achieved through targeted disruption of their genes, is not compatible with murine embryogenesis. Finally, the first reports of human diseases apparently caused by mutations or rearrangements of the genes involved in polyamine metabolism have appeared.