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PubMed1982

Induction of choline kinase by polycyclic aromatic hydrocarbons in rat liver. II. Its relation to net phosphatidylcholine biosynthesis.

The effect of a single dose (50 mg/kg body weight) of 3-methylcholanthrene on de novo phosphatidylcholine biosynthetic activities in rat liver was studied both in a cell-free system and with slice experiments. 3-Methylcholanthrene caused a significant depression of either [methyl-14C]choline or [2-(3)H]glycerol incorporation into phosphatidylcholine when the precursor was incubated with liver slices. At the same time, there occurred a significant accumulation of radioactivity in either cholinephosphate or diacylglycerol molecule from [14C]choline or [3H]glycerol, respectively, suggesting that 3-methylcholanthrene could cause an inhibitory effect on hepatic phosphatidylcholine synthesis at the cholinephosphotransferase or/and cholinephosphate cytidylyltransferase step. Subsequent studies, where the activities of the three enzymes involved in de novo phosphatidylcholine synthesis were compared between control and 3-methylcholanthrene-pretreated rat liver subcellular fractions, demonstrated that the cholinephosphotransferase step could be the site of inhibition by 3-methylcholanthrene. On the other hand, 3-methylcholanthrene caused a significant induction of choline kinase activity in a time-dependent manner and, at the same time, the cholinephosphate pool size in liver cytosol was enlarged 2-3-fold when compared to the respective control. The overall results suggested strongly that 3-methylcholanthrene causes the counteractive effects on the de novo phosphatidylcholine biosynthesis, induction of choline kinase activity and inhibition of cholinephosphotransferase activity, both of which could participate in a concomitant increase in cholinephosphate pool size in rat liver.

Animals↗
PubMed1990

Purification and properties of choline kinase from rat brain.

A blue-dye column separated rat brain choline kinase (EC 2.7.1.32) into two peaks, very likely corresponding to distinct isozymes. The major-peak enzyme was purified 15,000-fold to homogeneity. The final specific activity was approx. 40 mumol.min-1.mg-1. This is 10-times higher than that reported for the enzymes from lung and kidney. The purified enzyme gave a single 44 kDa protein band on sodium dodecyl sulfate polyacrylamide gel electrophoresis. Analytical gel-filtration showed that the native enzyme had a molecular weight of 90,000 and a Stokes radius of 4.2 nm. The sedimentation coefficient was deduced to be 4.8 S and the molecular weight 87,600 by sucrose-density-gradient centrifugation. Hence, the native enzyme appears to be a dimer. The apparent Km values for ATP and choline were 1.0 mM and 14 microM, respectively. At high choline concentrations, the enzyme showed deviation from Michaelis-Menten kinetics. The enzyme was active in a high pH range and utilized a variety of amino alcohols structurally related to choline, including ethanolamine, N-methylethanolamine and N,N-dimethylethanolamine as substrates. Spermine and spermidine stimulated the enzyme by decreasing the apparent Km for ATP and increasing Vmax. Although less efficiently, monovalent cations such as NH4+, K+, Li+ and Na+ and quaternary amines such as carpronium, chlorocholine and acetylcholine were also stimulatory.

Amines↗
PubMed2005

A rostrocaudal muscular dystrophy caused by a defect in choline kinase beta, the first enzyme in phosphatidylcholine biosynthesis.

Muscular dystrophies include a diverse group of genetically heterogeneous disorders that together affect 1 in 2000 births worldwide. The diseases are characterized by progressive muscle weakness and wasting that lead to severe disability and often premature death. Rostrocaudal muscular dystrophy (rmd) is a new recessive mouse mutation that causes a rapidly progressive muscular dystrophy and a neonatal forelimb bone deformity. The rmd mutation is a 1.6-kb intragenic deletion within the choline kinase beta (Chkb) gene, resulting in a complete loss of CHKB protein and enzymatic activity. CHKB is one of two mammalian choline kinase (CHK) enzymes (alpha and beta) that catalyze the phosphorylation of choline to phosphocholine in the biosynthesis of the major membrane phospholipid phosphatidylcholine. While mutant rmd mice show a dramatic decrease of CHK activity in all tissues, the dystrophy is only evident in skeletal muscle tissues in an unusual rostral-to-caudal gradient. Minor membrane disruption similar to dysferlinopathies suggest that membrane fusion defects may underlie this dystrophy, because severe membrane disruptions are not evident as determined by creatine kinase levels, Evans Blue infiltration, and unaltered levels of proteins in the dystrophin-glycoprotein complex. The rmd mutant mouse offers the first demonstration of a defect in a phospholipid biosynthetic enzyme causing muscular dystrophy, representing a unique model for understanding mechanisms of muscle degeneration.

Animals↗
PubMed2003

Bispyridinium cyclophanes: novel templates for human choline kinase inhibitors.

The synthesis and biological activities of four novel bispyridinium cyclophanes as choline kinase (ChoK) inhibitors are presented. Their synthetic methodology has been optimized according to dilution, temperature, and reaction time and provides pure bispyridinium cyclophanes in high yields very easily. One of these cyclophanes (6, 4,8-diaza-3(1,4),9(4,1)-dipyridina-1(1,4),6(1,3)-dibenzenacyclodecaphan-3(1),9(1)-bis(ilium) dibromide) has an IC(50(ChoK)) of 0.3 microM and is the most potent human ChoK inhibitor described to date.

Antineoplastic Agents↗
PubMed2002

Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy.

Choline kinase (ChoK) and its product, phosphocholine (PCho), have been implicated in human carcinogenesis. Inhibition of this enzyme has been shown to be an efficient antitumor strategy in vivo. The aim of this study was to assess the relationship between the regulation of ChoK and clinical features in patients with breast cancer. To that end, normal and tumoral tissues from 53 patients with breast carcinomas were analysed for ChoK activity and expression, and compared to some clinical parameters. We report a relevant increase in ChoK activity in 38.5% of the tumoral tissues analysed when compared to the normal levels in healthy tissues. Furthermore, some clinical features were found significant versus ChoK status. First, an association of choline enzymatic activity with histological tumor grade was observed (P<0.001). In addition, increased ChoK activity was also associated with ER-negative breast carcinomas (P=0.037). A significant association between ChoK overexpression and both high histologic tumor grade (P=0.017) and ER-negative tumors (P=0.003) was found. Finally, ChoK overexpression was found in 17% of the samples and all corresponded with those that display the highest increase in ChoK activity (P<0.001). Here we provide evidence that ChoK may be related to the development of human breast cancer, suggesting that this finding may constitute the basis for the development of a novel antitumoral strategy for these patients.

Adult↗
PubMed2004

Towards a model for the inhibition of choline kinase by a new type of inhibitor.

Bispyridinium cyclophanes are novel templates for human choline kinase inhibitors. Molecular modelling of these compounds suggests three anchorage places at the binding site of the enzyme: (i) two anionic centres of the enzyme active site separated from each other at a distance of approximately 6.2 A that bind the two positively charged nitrogen atoms; (ii) a wide hydrophobic pocket that is fulfilled by the upper linker, the benzene ring that links the two amino groups; and (iii) a smaller hydrophobic pocket that can accommodate the lower benzene ring that links both benzylic carbons. This study may be useful for the development of more potent inhibitors of the enzyme.

Choline Kinase↗
PubMed2004

Influence of the linker in bispyridium compounds on the inhibition of human choline kinase.

Studies have been aimed to establish the structure-activity relationship that define choline kinase (ChoK) inhibitory potency and antiproliferative activity of a set of 25 bispyridinium compounds with electron-releasing groups at position 4. Here we report that, according to their inhibitory activities against human ChoK, the enzymatic inhibitory potency is closely related to the size of the linker, the 3,3'-biphenyl moiety being the most suitable. The N-methylanilino and its derivatives, 4-chloro-N-methylanilino and 3,5-dichloro-N-methylanilino, render higher ChoK inhibitory and antiproliferative activities against the HT-29 human colon cancer cell line.

Antineoplastic Agents↗
PubMed2003

QSAR-derived choline kinase inhibitors: how rational can antiproliferative drug design be?

This review presents an overview of Choline Kinase (ChoK) inhibitors with antiproliferative activity. The consideration of ChoK as a novel target for the development of new anticancer drugs is justified. The synthesis of several derivatives based on structural modifications of hemicholinium-3 (HC-3) is not accompanied by potentiation of the neurological toxicity of HC-3. The increment of both ChoK inhibitory and antiproliferative activities was successfully obtained by the two following changes: a) substitution of the oxazonium moiety of HC-3 by several aromatic heterocycles, and b) using the 1,2-ethylene(bisbenzyl) moiety instead of the 4,4'-biphenyl fragment. In an attempt to understand the ChoK inhibitory activity, a quantitative structure-activity relationship was developed. The QSAR equations have described the forces involved in quantitative terms. The electron characteristic of the substituent at position 4 of the heterocycle and the lipophilic character of the whole molecule were found to significantly affect the antitumour activity in compounds 17-95. Trispyridinium compounds 91-95 are more potent than the bispyridinium ones 87-89 as ChoK inhibitors. Nevertheless, 91-95 are less active than 87-89 as antiproliferative agents because the latter show better lipophilicities to cross the cytosolic membranes. Inhibition of the growth of human tumours in nude mice has been demonstrated: Antitumour activity of compound 64 against human HT-29 produced a decrease of up to 70% in the size of the tumour in nude mice. These results indicate that ChoK can be used as a general target for anticancer drug design against Ras-dependent tumourigenesis.

Animals↗
PubMed1995

Reciprocal regulation of choline acetyltransferase and choline kinase in sympathetic neurons during cholinergic differentiation.

The regulation of the synthesis of acetylcholine and phosphatidylcholine in rat sympathetic neurons was examined in the context of cholinergic differentiation. We demonstrate that the activities of choline acetyltransferase (ChAT) and choline kinase (CK) are inversely affected by treatment of sympathetic neurons with retinoic acid, utilized as an agent that induces cholinergic differentiation. Whereas ChAT specific activity increased 2- to 4-fold after 12 days of treatment with 5 microM retinoic acid, CK specific activity decreased by 25-30%. These changes in enzyme activities were essentially reflected in the incorporation of [methyl-3H]choline into ACh and the metabolites of the CDP-choline pathway for phosphatidylcholine synthesis. When sympathetic neurons were treated under high potassium conditions (50 mM) for 12 days, the specific activity of CK increased 1.3-fold whereas the activity of ChAT decreased by up to 90%. Furthermore, experiments in which the incorporation of [methyl-3H]choline into ACh and the metabolites of the CDP-choline pathway was measured in the absence of Na+ or in the presence of hemicholinium-3 (HC-3), demonstrate that CK has access to the same pool of choline utilized by ChAT. These results provide evidence that the activities of ChAT and CK may be inversely regulated during the process of cholinergic differentiation.

Acetylcholine↗
PubMed1994

Expression of the ceramide galactosyltransferase gene during myelination of the mouse nervous system. Comparison with the genes encoding myelin basic proteins, choline kinase and CTP:phosphocholine cytidylyltransferase.

The present study documents the patterns of mRNA expression for the ceramide galactosyltransferase (CGT), the CTP:phosphocholine cytidylyltransferase (CT), and the choline kinase (CK) during the myelination period of the mouse central nervous system (CNS) and peripheral nervous system (PNS). Using the Northern blot technique with densitometric analyses, we show that the CK gene is not developmentally regulated during the period studied, whereas a peak of expression of the CT gene is observed around day 10. On the other hand, the expression of the CGT gene is similar to that of the MBP gene in the CNS and the PNS. Therefore, the synthesis of the galactosylceramides during the myelination period seems to be controlled at the level of the expression of the CGT gene. These results were compared to those of a neurological mutant, the trembler mouse, whose PNS myelination is deficient. Our results clearly indicate that the deficit in the accumulation of the galactosylceramides documented for this mutant is well correlated to a reduced CGT gene expression.

Animals↗
PubMed1999

In vivo antitumor activity of choline kinase inhibitors: a novel target for anticancer drug discovery.

Transformation by some oncogenes is associated with increased activity of choline kinase (ChoK), resulting in elevated constitutive levels of phosphorylcholine, a proposed second messenger required for DNA synthesis induced by growth factors. Here we describe the characterization of ChoK inhibitors with antiproliferative properties against human tumor-derived cell lines. The new molecules were tolerated in mice at doses that showed in vivo antitumor activity against human tumor xenografts derived from HT-29 and A431 cell lines implanted s.c. in nude mice. This first generation of inhibitors provides in vivo evidence that blockade of phosphorylcholine production is a valid strategy for the development of new anticancer agents, opening a new avenue for the development of antitumor drugs with a novel mechanism of action.

Adenocarcinoma↗
PubMed2004

Regulation of phosphatidylcholine biosynthesis under salt stress involves choline kinases in Arabidopsis thaliana.

Increasing evidence suggests a major role for phosphatidylcholine (PC) in plant stress adaptation. The present work investigated the regulation of choline, PC and interconnected phosphatidylethanolamine biosynthesis in Arabidopsis thaliana L. as a function of cold- and salt- or mannitol-mediated hyperosmotic stresses. While PC synthesis is accelerated in both salt- and cold-treated plants, the choline kinase (CK) and phosphocholine cytidylyltransferase genes are oppositely regulated with respect to these abiotic treatments. Salt stress also stimulates CK activity in vitro. A possible regulatory role of CK in stimulating PC biosynthesis rate in salt-stressed plants is discussed.

Arabidopsis↗
PubMed2004

Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action.

Choline kinase (ChoK, E.C. 2.7.1.32) is involved in the synthesis of phosphatidylcholine (PC), and has been found to be increased in human tumors and tumor-derived cell lines. Furthermore, ChoK inhibitors have been reported to show a potent and selective antitumoral activity both in vitro and in vivo. Here, we provide the basis for a rational understanding of the antitumoral activity of ChoK inhibitors. In normal cells, blockage of de novo phosphorylcholine (PCho) synthesis by inhibition of ChoK promotes the dephosphorylation of pRb, resulting in a reversible cell cycle arrest at G0/G1 phase. In contrast, ChoK inhibition in tumor cells renders cells unable to arrest in G0/G1 as manifested by a lack of pRb dephosphorylation. Furthermore, tumor cells specifically suffer a drastic wobble in the metabolism of main membrane lipids PC and sphingomyelin (SM). This lipid disruption results in the enlargement of the intracellular levels of ceramides. As a consequence, normal cells remain unaffected, but tumor cells are promoted to apoptosis. Thus, we provide in this study the rationale for the potential clinical use of ChoK inhibitors.

Antineoplastic Agents↗
PubMed2005

Inhibition of choline kinase renders a highly selective cytotoxic effect in tumour cells through a mitochondrial independent mechanism.

Tumour cells are frequently altered in their phospholipid metabolism. Choline kinase (ChoK, E.C. 2.7.1.32) activity, the first enzyme involved in the synthesis of phosphatidylcholine, is increased in a large number of human tumours and tumour-derived cell lines. We have previously reported that MN58b, a specific inhibitor of ChoK, has anti-tumoral activity. Here we show the high specificity of MN58b as a cytotoxic drug towards tumour cells, and explore further the basis of its mechanism of action in order to provide a rational understanding for its antitumoral activity. A dramatic difference in the response to the treatment of primary, normal and non-tumorigenic human cells when compared to tumour-derived cell lines was observed. In normal cells, blockage of de novo PCho synthesis by MN58b results in a reversible cell cycle arrest at G0/G1 phase. In contrast, ChoK inhibition in tumour cells promotes the induction of apoptosis. This effect depends on the cell cycle phase, being G1 the critical phase. Regarding the mechanism of apoptosis engagement, a loss of mitochondrial potential was observed 10-20 min after cytochrome c release, but caspase 3 activation preceded the loss of mitochondrial potential, indicating that activation of caspase 3 is independent of cytochrome c release. Our results are consistent with a non-intrinsic process as the mechanism underlying the induction of apoptosis by ChoK inhibition in tumoral cells.

Apoptosis↗
PubMed2006

(Q)SAR studies to design new human choline kinase inhibitors as antiproliferative drugs.

Most of the signal transduction pathways are mediated by protein kinases regulating every aspect of cell function. Mutations which deregulate their expression or their function or both result in cancers. Therefore, protein kinase inhibitors have become the focus of development of new therapies for cancer. A comprehensive review of Choline kinase (ChoK) was published by us in 2003. Since then, molecular information of ChoK inhibitors has been accumulated. In this review, we intend to summarize the new lines of evidence that will include the design of the most active antiproliferative agents so far described against ChoK. Studies have been aimed at the establishment of structure-activity relationships and the structural parameters that define ChoK inhibitory and antiproliferative activities of a set of twenty-five acyclic biscationic pyridophane and forty acyclic biscationic quinolinephane compounds. The corresponding QSAR equation was obtained for the whole set of bisquinolinium compounds for the antiproliferative activity, taking into consideration the electronic parameter sigma(R) of R(4), the molar refractivity (MR) of R(8), and the lipophilic parameters clog P and pi(linker). The most potent antiproliferative agent shows an IC(50) = 0.45 microM, predicted by the QSAR equation, whilst its experimental value is IC(50) = 0.20 microM. Finally, toxicity assays were performed for the most promising compounds because of their interesting antiproliferative activities [IC(50 HT-29) = 0.70, 0.80, 1.50 and 1.90 microM] and low toxicity [LD(50) = 16.7, 12.5, > 25 and > 20 mg/kg of mouse]. These biological activities justify further analysis for antitumoral assays under in vivo conditions.

Animals↗
PubMed2005

Symmetrical bis-quinolinium compounds: new human choline kinase inhibitors with antiproliferative activity against the HT-29 cell line.

Studies have been aimed at the establishment of structure-activity relationships that define choline kinase inhibitory and antiproliferative activities of 40 bisquinolinium compounds. These derivatives have electron-releasing groups at position 4 of the quinolinium ring. It is found that the enzymatic inhibition is closely related to the size of the linker, the 3,3'-biphenyl moiety being the most suitable. On the other hand, the antiproliferative activity against the HT-29 cancer cell line is less influenced by the linker type and by substituent R(4). The corresponding QSAR equation was obtained for the whole set of compounds for the antiproliferative activity, the electronic parameter sigma(R) of R(4), the molar refractivity of R(8), and the lipophilic parameters clog P and pi(linker). The most potent antiproliferative agent so far described is 40 for which an IC(50) = 0.45 microM was predicted by the QSAR equation, while its experimental value is IC(50) = 0.20 microM.

Biphenyl Compounds↗
PubMed1998

The choline kinase inhibitor hemicholinium-3 can inhibit mitogen-induced DNA synthesis independent of its effect on phosphocholine formation.

In NIH 3T3 cells, phosphocholine (PCho) stimulates mitogenesis in synergism with insulin, ATP, and sphingosine-1-phosphate (S1P) via an extracellular target. Intracellular PCho also has been suggested to mediate the mitogenic effects of fibroblast growth factor (FGF) and several other growth factors based, in part, on the observed inhibition of growth factor-induced mitogenesis by the choline kinase inhibitor hemicholinium-3 (HC-3). Here we examined the specificity of HC-3 effects on mitogenesis in serum-starved NIH 3T3 and Swiss 3T3 cells. In both cell lines, FGF greatly enhanced DNA synthesis in a medium containing 28 microM choline, and it also stimulated the formation of -14C-PCho from both 50 microM and 5 mM [14C]choline. HC-3 (2 mM) inhibited basal or FGF-induced formation of [14C]PCho and [14C]phosphatidylcholine as well as the uptake of -14C-choline only at the 50 microM, but not the 5 mM, concentration of [14C]choline. In addition, HC-3 (1 mM) from three different sources (95-99.9% purity) inhibited FGF-stimulated DNA synthesis by 53-58% which was not reversed by 5 mM choline. The choline analogue dimethylethanolamine (1 mM) also inhibited FGF-stimulated formation of [14C]PCho from 50 microM -14C-choline, but it had no effect on FGF-induced DNA synthesis. Of the other growth regulators examined, synergistic stimulation of DNA synthesis by extracellular PCho and S1P or PCho and ATP via choline kinase-independent mechanisms was inhibited by 2 mM HC-3. However, HC-3 failed to inhibit the synergistic mitogenic effects of PCho and insulin or S1P and insulin. The results suggest that FGF-induced mitogenesis does not require PCho formation and that HC-3 can inhibit DNA synthesis independent of its inhibitory effects on choline metabolism.

3T3 Cells↗
PubMed2000

QSAR of 1,1'-(1,2-ethylenebisbenzyl)bis(4-substitutedpyridinium) dibromides as choline kinase inhibitors: a different approach for antiproliferative drug design.

Ten new structures of a series of the title compounds were synthesized and screened for their activity to inhibit choline kinase under ex vivo conditions. Their inhibitory potency correlates with the 13C chemical shifts (in CD3OD) of the methylene group bearing the positively charged nitrogen. The inhibitory effect on proliferation against the HT-29 cell line is strongly dependent on its ability to inhibit the production of phosphorylcholine.

Cell Division↗