Chalcone tetramers, lophirachalcone and alatachalcone, from Lophira alata as possible anti-tumor promoters.
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Two chalcone tetramers were isolated as inhibitors of Epstein-Barr virus (EBV)-activation induced by a tumor promoter, teleocidin B-4, from a medicinal plant in tropical west Africa, Lophira alata (Ochnaceae). One of them was identified as lophirachalcone. The other, named alatachalcone, was new, and the structure was determined by spectral properties. Both compounds also showed potent inhibitory activities against teleocidin B-4-induced inflammation on mouse ear. In an initiation-promotion experiment on mouse skin, alatachalcone (16 nmol) significantly inhibited tumor promotion caused by 12-O-tetradecanoylphorbol-13-acetate (TPA, 1.6 nmol). (+info)
Acquisition of a growth-inhibitory response to phorbol ester involves DNA damage.
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TPA (12-O-tetradecanoylphorbol-13-acetate), a potent tumor promoter, has been shown to stimulate or inhibit cell growth depending on the cell type investigated. We recently found that RT101 cells, a transformed mouse JB6 epidermal cell line, acquired a greater growth inhibition response to TPA during conventional subcultivation. The growth of low-passage RT101 cells was slightly inhibited by TPA in monolayer culture but stimulated in soft agar. In contrast, the growth of high-passage cells was greatly inhibited by TPA in both monolayer culture and in soft agar. Inhibition was dose dependent, directly correlated with protein kinase C-activating activities of tumor promoters, and was found to be reversible. TPA-treated high-passage cells were greatly reduced in volume, showed extensive abnormal mitoses, and were more susceptible to detachment. High-passage cells were also found to be less tumorigenic as indicated by in vivo tumorigenicity assay in nude mice. TPA treatment rendered cells still less tumorigenic in the case of both cell lines. The mechanism for acquisition of increased sensitivity to TPA of RT101 cells during subculture was investigated; it involved nonrandom DNA damage and detachment of nonviable cells. The results suggest the possibility that early-passage RT101 cells contained two subpopulations, one TPA-sensitive and one TPA-resistant population. Conventional subcultivation may have selected for the former subpopulation. The sensitive subpopulation may have been irreversibly inhibited as a result of TPA-induced cell killing, possibly apoptosis. (+info)
Pharmacology and toxicology of pahayokolide A, a bioactive metabolite from a freshwater species of Lyngbya isolated from the Florida Everglades.
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The genus of filamentous cyanobacteria, Lyngbya, has been found to be a rich source of bioactive metabolites. However, identification of such compounds from Lyngbya has largely focused on a few marine representatives. Here, we report on the pharmacology and toxicology of pahayokolide A from a freshwater isolate, Lyngbya sp. strain 15-2, from the Florida Everglades. Specifically, we investigated inhibition of microbial representatives and mammalian cell lines, as well as toxicity of the compound to both invertebrate and vertebrate models. Pahayokolide A inhibited representatives of Bacillus, as well as the yeast, Saccharomyces cerevisiae. Interestingly, the compound also inhibited several representatives of green algae that were also isolated from the Everglades. Pahayokolide A was shown to inhibit a number of cancer cell lines over a range of concentrations (IC50 varied from 2.13 to 44.57 microM) depending on the cell-type. When tested against brine shrimp, pahayokolide was only marginally toxic at the highest concentrations tested (1 mg/mL). The compound was, however, acutely toxic to zebrafish embryos (LC50=2.15 microM). Possible biomedical and environmental health aspects of the pahayokolides remain to be investigated; however, the identification of bioactive metabolites such as these demonstrates the potential of the Florida Everglades as source of new toxins and drugs. (+info)
Role of lymphotoxin in expression of interleukin 6 in human fibroblasts. Stimulation and regulation.
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IL-6 is a cytokine with a number of biological functions, including stimulation of immunoglobulin synthesis and proliferation of early hematopoietic stem cells. We showed that lymphotoxin stimulated accumulation of IL-6 mRNA in human fibroblasts (W138) in a dose-responsive fashion; tumor necrosis factor-alpha (TNF-alpha) was about threefold more potent than lymphotoxin. Further experiments suggested that stimulation by lymphotoxin was independent of protein kinase C activity, did not require new protein synthesis, and was at least in part a result of increased stabilization of IL-6 mRNA. t1/2 of the IL-6 transcripts increased from 0.3 h in unstimulated cells to 0.85 h in cells stimulated with lymphotoxin. In addition, stimulators of protein kinase C, including phorbol esters and teleocidin, enhanced accumulation of IL-6 mRNA. Cycloheximide (CHX), inhibitor of protein synthesis, also markedly increased levels of IL-6 mRNA. Both CHX and activators of protein kinase C increased by greater than 16-fold the stability of IL-6 mRNA. Further, dose-response studies showed that sodium fluoride (NaF), activator of G-binding proteins, and ouabain, inhibitor of Na+/H+ pump, increased levels of IL-6 mRNA. NaF stimulated IL-6 mRNA levels independent of protein kinase C activity. These results suggest that stimulators of several pathways of signal transduction increase levels of IL-6 mRNA and posttranscriptional stabilization is, in part, the mechanism that many of these signals, including lymphotoxin, use to increase levels of IL-6 RNA. (+info)
Vacuole formation and cytokeratin rearrangement of hepatoma cells induced by teleocidin are not associated with down-regulation of protein kinase C.
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PLC/PRF/5 human hepatoma cells cultured with teleocidin reduced the rate of cell proliferation and were transformed into large cells with many vacuole-like subcellular structures. In these vacuolated cells, the protein content per cell increased without changing the total cellular protein synthesis. Cytokeratin was one of the proteins which increased quantitatively. This intermediate filament formed fibrous network structures throughout the enlarged cytoplasm. The assembly of other cytoskeletal proteins such as actin, tubulin, and vimentin was not altered remarkably, suggesting that teleocidin morphologically transformed the hepatoma cells by changing the assembly of cytokeratin protein selectively. On the other hand, the alterations of cell proliferation, cell morphology, and cytokeratin assembly induced by teleocidin were not associated with either down-regulation of protein kinase C or reduced number of epidermal growth factor receptors. In addition, these teleocidin effects were not mimicked by the protein kinase C agonist 1-oleoyl-2-acetylglycerol or inhibited by the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine. From these results it can be speculated that the morphological transformation and reduced cell proliferation induced by teleocidin may be mediated by still unknown mechanisms unrelated to protein kinase C. (+info)
Structures of pahayokolides A and B, cyclic peptides from a Lyngbya sp.
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The isolation and structure elucidation of two cyclic peptides, pahayokolides A (1) and B (2), is described. Structural features determined for these compounds include a pendent N-acetyl-N-methyl leucine, both E- and Z-dehydrobutyrines, a homophenylalanine, and an unusual polyhydroxy amino acid that is most likely of mixed polyketide synthase/nonribosomal peptide synthase origin. These peptides were purified from a new species of cyanobacteria of the genus Lyngbya, which was isolated from a periphyton mat from the Florida Everglades. (+info)
Natural products chemistry and taxonomy of the marine cyanobacterium Blennothrix cantharidosmum.
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