Ukrain - a new cancer cure? A systematic review of randomised clinical trials.
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BACKGROUND: Ukrain is an anticancer drug based on the extract of the plant Chelidonium majus L. Numerous pre-clinical and clinical investigations seem to suggest that Ukrain is pharmacologically active and clinically effective. We wanted therefore to critically evaluate the clinical trial data in the form of a systematic review. METHODS: Seven electronic databases were searched for all relevant randomised clinical trials. Data were extracted and validated by both authors, tabulated and summarised narratively. The methodological quality was assessed with the Jadad score. RESULTS: Seven trials met our inclusion criteria. Without exception, their findings suggest that Ukrain has curative effects on a range of cancers. However, the methodological quality of most studies was poor. In addition, the interpretation of several trials was impeded by other problems. CONCLUSION: The data from randomised clinical trials suggest Ukrain to have potential as an anticancer drug. However, numerous caveats prevent a positive conclusion, and independent rigorous studies are urgently needed. (+info)
Molecular recognition of nucleic acids: coralyne binds strongly to poly(A).
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The small molecule coralyne was found to bind preferentially and strongly to single-stranded poly(A) with an apparent association constant (Ka) of (1.8+/-0.3) x 10(6)M(-1). Binding of coralyne to poly(A) is predominantly enthalpically driven with a stoichiometry of one coralyne per four adenine bases. Poly(A) forms a coralyne dependent secondary structure with a melting temperature of 60 degrees C, for the conditions of our study. (+info)
Regulation of glutamate level in rat brain through activation of glutamate dehydrogenase by Corydalis ternata.
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When treated with protopine and alkalized extracts of the tuber of Corydalis ternata for one year, significant decrease in glutamate level and increase in glutamate dehydrogenase (GDH) activity was observed in rat brains. The expression of GDH between the two groups remained unchanged as determined by Western and Northern blot analysis, suggesting a post-translational regulation of GDH activity in alkalized extracts treated rat brains. The stimulatory effects of alkalized extracts and protopine on the GDH activity was further examined in vitro with two types of human GDH isozymes, hGDH1 (house-keeping GDH) and hGDH2 (nerve-specific GDH). Alkalized extracts and protopine activated the human GDH isozymes up to 4.8-fold. hGDH2 (nerve- specific GDH) was more sensitively affected by 1 mM ADP than hGDH1 (house-keeping GDH) on the activation by alkalized extracts. Studies with cassette mutagenesis at ADP-binding site showed that hGDH2 was more sensitively regulated by ADP than hGDH1 on the activation by Corydalis ternata. Our results suggest that prolonged exposure to Corydalis ternata may be one of the ways to regulate glutamate concentration in brain through the activation of GDH. (+info)
Proapoptotic activity of Ukrain is based on Chelidonium majus L. alkaloids and mediated via a mitochondrial death pathway.
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BACKGROUND: The anticancer drug Ukrain (NSC-631570) which has been specified by the manufacturer as semisynthetic derivative of the Chelidonium majus L. alkaloid chelidonine and the alkylans thiotepa was reported to exert selective cytotoxic effects on human tumour cell lines in vitro. Few clinical trials suggest beneficial effects in the treatment of human cancer. Aim of the present study was to elucidate the importance of apoptosis induction for the antineoplastic activity of Ukrain, to define the molecular mechanism of its cytotoxic effects and to identify its active constituents by mass spectrometry. METHODS: Apoptosis induction was analysed in a Jurkat T-lymphoma cell model by fluorescence microscopy (chromatin condensation and nuclear fragmentation), flow cytometry (cellular shrinkage, depolarisation of the mitochondrial membrane potential, caspase-activation) and Western blot analysis (caspase-activation). Composition of Ukrain was analysed by mass spectrometry and LC-MS coupling. RESULTS: Ukrain turned out to be a potent inducer of apoptosis. Mechanistic analyses revealed that Ukrain induced depolarisation of the mitochondrial membrane potential and activation of caspases. Lack of caspase-8, expression of cFLIP-L and resistance to death receptor ligand-induced apoptosis failed to inhibit Ukrain-induced apoptosis while lack of FADD caused a delay but not abrogation of Ukrain-induced apoptosis pointing to a death receptor independent signalling pathway. In contrast, the broad spectrum caspase-inhibitor zVAD-fmk blocked Ukrain-induced cell death. Moreover, over-expression of Bcl-2 or Bcl-xL and expression of dominant negative caspase-9 partially reduced Ukrain-induced apoptosis pointing to Bcl-2 controlled mitochondrial signalling events. However, mass spectrometric analysis of Ukrain failed to detect the suggested trimeric chelidonine thiophosphortriamide or putative dimeric or monomeric chelidonine thiophosphortriamide intermediates from chemical synthesis. Instead, the Chelidonium majus L. alkaloids chelidonine, sanguinarine, chelerythrine, protopine and allocryptopine were identified as major components of Ukrain. Apart from sanguinarine and chelerythrine, chelidonine turned out to be a potent inducer of apoptosis triggering cell death at concentrations of 0.001 mM, while protopine and allocryptopine were less effective. Similar to Ukrain, apoptosis signalling of chelidonine involved Bcl-2 controlled mitochondrial alterations and caspase-activation. CONCLUSION: The potent proapoptotic effects of Ukrain are not due to the suggested "Ukrain-molecule" but to the cytotoxic efficacy of Chelidonium majus L. alkaloids including chelidonine. (+info)
A gold nanoparticle based approach for screening triplex DNA binders.
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Nanoparticle assemblies interconnected with DNA triple helixes can be used to colorimetrically screen for triplex DNA binding molecules and simultaneously determine their relative binding affinities based on melting temperatures. Nanoparticles assemble only when DNA triple helixes form between DNA from two different particles and a third strand of free DNA. In addition, the triple helix structure is unstable at room temperature and only forms in the presence of triplex DNA binding molecules which stabilize the triple helix. The resulting melting transition of the nanoparticle assembly is much sharper and at a significantly higher Tm than the analogous triplex structure without nanoparticles. Upon nanoparticle assembly, a concomitant red-to-blue color change occurs. The assembly process and color change do not occur in the presence of duplex DNA binders and therefore provide a significantly better screening process for triplex DNA binding molecules compared to standard methods. (+info)
NF-kappaB does not influence the induction of apoptosis by Ukrain.
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Ukrain is a reaction product of different alkaloids from Chelidonium majus L. (celandine) conjugated with thiophosphoric acid. It has immunoregulatory effects on T lymphocyte subsets and cytotoxic and cytostatic effects on various malignant cells. Although Ukrain has been reported to induce alterations in the cell cycle and tubulin polymerization, the specific cellular target has not been described. Since antineoplasic agents induce NF-kappaB and their effects are regulated by this transcription factor, we investigated its possible participation in the apoptotic effects of Ukrain. Ukrain induced apoptosis in a panel of cancer cell lines by activating the intrinsic cell death pathway, as demonstrated by the cleavage of caspase 9 and the upregulation and cleavage of caspase 3. The effect was reversible, since long exposures (24 hours or more) were needed, as verified by clonogenic assays. Gene reporter assays showed that Ukrain activated NF-kappa B. Nevertheless, this activation was not required for, and did not modulate, the Ukrain effect: neither blockage of activation by a dominant negative version of Ikappa-B alpha or a Bcl-3 siRNA, nor activation of the pathway by overexpression of IKK2, changed the response to the drug. In conclusion, Ukrain induced apoptosis in HeLa cervical cancer cells by activating the intrinsic pathway. In contrast to other antineoplasic drugs, the effects of Ukrain were not regulated by NF-kappa B. (+info)
l-tetrahydropalmatine increases leucine enkephalin levels in corpus striatum of rats.
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The effect of chronic l-tetrahydropalmatine (l-THP) administration on the level of leucine enkephalin (Leu-Enk) in rat corpus striatum was studied. After l-THP sc injection once daily for 2 wk, the striatal Leu-Enk level was elevated dose-dependently. However, a single injection of l-THP failed to change the Leu-Enk level. When rats received sc Sch-23390, a selective D1 antagonist, 15 nmol.kg-1 tid for 2 wk, striatal content of Leu-Enk increased from 0.17 +/- SD 0.03 ng.mg-1 tissue in control group to 0.23 +/- SD 0.05 ng.mg-1 tissue in Sch-23390 group (n = 8, P less than 0.05). Sulpiride (Sul), a selective D2 antagonist, 140 mumol.kg-1 sc given bid for 2 wk had no significant effect on the striatal Leu-Enk content. The results suggested that the blockade of D1 receptors by l-THP might be responsible for the increase of the striatal Leu-Enk content in rat. (+info)
Molecular cloning and characterization of tetrahydroprotoberberine cis-N-methyltransferase, an enzyme involved in alkaloid biosynthesis in opium poppy.
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S-Adenosyl-l-methionine:tetrahydroprotoberberine cis-N-methyltransferase (EC 2.1.1.122) catalyzes the conversion of (S)-stylopine to the quaternary ammonium alkaloid, (S)-cis-N-methylstylopine, as a key step in the biosynthesis of protopine and benzophenanthridine alkaloids in plants. A full-length cDNA encoding a protein exhibiting 45 and 48% amino acid identity with coclaurine N-methyltransferase from Papaver somniferum (opium poppy) and Coptis japonica, respectively, was identified in an elicitor-treated opium poppy cell culture expressed sequence tag data base. Phylogenetic analysis showed that the protein belongs to a unique clade of enzymes that includes coclaurine N-methyltransferase, the predicated translation products of the Arabidopsis thaliana genes, At4g33110 and At4g33120, and bacterial S-adenosyl-L-methionine-dependent cyclopropane fatty acid synthases. Expression of the cDNA in Escherichia coli produced a recombinant enzyme able to convert the protoberberine alkaloids stylopine, canadine, and tetrahydropalmatine to their corresponding N-methylated derivatives. However, the protoberberine alkaloids tetrahydroxyberbine and scoulerine, and simple isoquinoline, benzylisoquinoline, and pavine alkaloids were not accepted as substrates, demonstrating the strict specificity of the enzyme. The apparent K(m) values for (R,S)-stylopine and S-adenosyl-L-methionine were 0.6 and 11.5 microm, respectively. TNMT gene transcripts and enzyme activity were detected in opium poppy seedlings and all mature plant organs and were induced in cultured opium poppy cells after treatment with a fungal elicitor. The enzyme was detected in cell cultures of other members of the Papaveraceae but not in species of related plant families that do not accumulate protopine and benzophenanthridine alkaloids. (+info)