The function of poliamine metabolism in prostate cancer

In many developed countries prostate cancer is the second leading cause of cancer related death in human population. Prostate tissue is characterized by the highest level of polyamines among organs in human body, and it is even higher in prostate carcinomas. These ubiquitous molecules are synthesized by prostate epithelium and are involved in many biochemical processes including cell proliferation, cell cycle regulation and protein synthesis. In this review we made the attempt to discuss the functions of polyamines, their involvement in apoptosis and potential role as molecular biomarker for prostate cancer. Also we present recent data on generation of drugs, in particular, cyclin dependent kinase inhibitor, developed for therapy of prostate cancer.Во многих развитых странах рак предстательной железы занимает первое место как причина смертности вследствие онкологических заболеваний. Ткань предстательной железы характеризуется наиболее высоким уровнем содержания полиаминов в сравнении с другими органами человека, причем в ткани карциномы простаты их содержание еще выше. Эти биомолекулы синтезируются эпителиальными клетками предстательной железы и принимают участие во многих биохимических процессах, включая пролиферацию клеток, регуляцию клеточного цикла и синтез белков. В обзоре обсуждаются функции полиаминов в клетке, их участие в процессах апоптоза и потенциальная роль в качестве биомаркеров при раке предстательной железы. Кроме того, приведены новые данные о разработке препаратов, в частности ингибитора циклинзависимой киназы, предназначенных для лечения рака предстательной железы

Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Folate (vitamin B9) is essential for cellular proliferation as it is involved in the biosynthesis of deoxythymidine monophosphate (dTMP) and s-adenosylmethionine (AdoMet). The link between folate depletion and the genesis and progression of cancers of epithelial origin is of high clinical relevance, but still unclear. We recently demonstrated that sensitivity to low folate availability is affected by the rate of polyamine biosynthesis, which is prominent in prostate cells. We, therefore, hypothesized that prostate cells might be highly susceptible to genetic, epigenetic and phenotypic changes consequent to folate restriction.</p> <p>Results</p> <p>We studied the consequences of long-term, mild folate depletion in a model comprised of three syngenic cell lines derived from the transgenic adenoma of the mouse prostate (TRAMP) model, recapitulating different stages of prostate cancer; benign, transformed and metastatic. High-performance liquid chromatography analysis demonstrated that mild folate depletion (100 nM) sufficed to induce imbalance in both the nucleotide and AdoMet pools in all prostate cell lines. Random oligonucleotide-primed synthesis (ROPS) revealed a significant increase in uracil misincorporation and DNA single strand breaks, while spectral karyotype analysis (SKY) identified five novel chromosomal rearrangements in cells grown with mild folate depletion. Using global approaches, we identified an increase in CpG island and histone methylation upon folate depletion despite unchanged levels of total 5-methylcytosine, indicating a broad effect of folate depletion on epigenetic regulation. These genomic changes coincided with phenotype changes in the prostate cells including increased anchorage-independent growth and reduced sensitivity to folate depletion.</p> <p>Conclusions</p> <p>This study demonstrates that prostate cells are highly susceptible to genetic and epigenetic changes consequent to mild folate depletion as compared to cells grown with supraphysiological amounts of folate (2 μM) routinely used in tissue culture. In addition, we elucidate for the first time the contribution of these aspects to consequent phenotype changes in epithelial cells. These results provide a strong rationale for studying the effects of folate manipulation on the prostate <it>in vivo</it>, where cells might be more sensitive to changes in folate status resulting from folate supplementation or antifolate therapeutic approaches.</p

Comparison of the effects of meta-topolin and other cytokinins on chlorophyll and protein contents and peroxidase activity in cucumber cotyledons

Cytokinins play an important role in controlling many of the processes that contribute to plant senescence. The aim of this study was to compare the effect of different cytokinins, especially the new aromatic cytokinin meta-topolin (mT), with kinetin (K), benzyladenine (BA), and zeatin (Z) on chlorophyll formation in etiolated cucumber cotyledons. Protein contents and peroxidase activities were also investigated. Exogenous application of cytokinins was effective in stimulating chlorophyll biosynthesis. mT was shown to be the most effective cytokinin in stimulating chlorophyll biosynthesis at low concentrations compared to the other cytokinins. MT treatments at 0.02-0.0002 mug/ml increased the amount of chlorophyll more than threefold compared with control cotyledons. BA stimulated the total chlorophyll content at 0.1-10 mug/ml concentrations, but inhibited at lower (0.01, 0.001 mug/ml) concentrations. K increased the chlorophyll amount at 1 mug/ml concentration to twice that of control cotyledons. Z stimulated the chlorophyll level at almost all the concentrations applied. The effects of the most effective concentrations of cytokinins used in this research on the chlorophyll level and on the protein content were examined. A doubling of protein content in 0.02 mug/ml-mT-treated cotyledons was observed, whereas Z, BA, and K increased the total protein to a lesser extent. BA was shown to have the greatest effect on peroxidase activity

Effect of spermine and cyclohexylamine on in vitro pollen germination and tube growth in Helianthus annuus

Naturally occurring polyamines (PA) are known to play a key role in growth and development of plants and animals. However, the role of these polycations in the development and germination of the pollen grain is not well understood. The effect of different concentrations of spermine (Spm) on pollen tube growth in Helianthus annuus was investigated. Spermine treatments in the 10(-7) to 10(-5) M range stimulated pollen tube growth starting in the first 15 min of the incubation period, while 10(-4) M Spm treatment resulted in inhibition of pollen tube elongation. The effect of cyclohexylamine (CHA), an inhibitor of Spm synthesis on pollen tube growth and germination percentage was also studied. Cyclohexylamine in the 0.5 x 10(-3) M to the 1.5 x 10(-3) M range inhibited pollen tube elongation. The relationship of B deficiency, excess B and PA effect on pollen germination and pollen tube growth were also investigated

DFT and MP2 based quantum mechanical calculations and a theoretical vibrational spectroscopic investigation on roscovitine, a potential drug to treat cancers

Theoretically possible stable conformers of free roscovitine molecule in its electronic ground state were searched by means of molecular dynamics and energy minimization calculations performed using the MM2 force field. Afterwards, geometry optimization and thermochemistry calculations were carried out at room temperature for each of the found minimum-energy conformers using the MP2 and DFT based electronic structure methods and different Pople-style basis sets. The results obtained from these calculations confirmed that the strong intramolecular hydrogen bonding between the purine-nitrogen and hydroxyl-hydrogen atoms plays an important role on the rigidity of roscovitine molecule and causes a dramatic reduction in the number of the possible stable conformers of this molecule at room temperature. Furthermore, the same calculation results also revealed that two of the found seven stable conformers are considerably more favorable in energy than the others and thus dominate the experimental room-temperature spectra of the molecule. In the light of the theoretical vibrational spectral data obtained for these two conformers, a successful assignment of the fundamental bands observed in the experimental IR and Raman spectra recorded at room temperature for solid roscovitine and for its ethanol solution is given, and the effects of the substitution and intramolecular hydrogen bonding on the fundamental bands associated with purine and phenyl group vibrations are discussed in detail. In the fitting of the calculated harmonic wavenumbers to the corresponding experimental wavenumbers, two different scaling procedures, called 'dual scale factors' and `Scaled Quantum Mechanical Force Field(SQMFF) methodology', were applied independently. Both procedures yielded results generally in good agreement with the experiment; however, the SQM FF methodology proved its superiority over the other. Copyright (C) 2010 John Wiley & Sons, Ltd