Tetradecanoylphorbol ester

As indicated in Chapters 5, 7 and 8, transcription can be switched on by a variety of signalling pathways. Thus, cAMP-mediated pathways generate phosphorylated CREB proteins that activate expression of particular proteins by binding to promoters called cAMP response elements (GREs). Similarly, Ca2+-dependent PKC activation results in phosphorylation of transcription factors that bind to and activate tetradecanoylphorbol ester response element (TRE) promoters. In the immune response bacterial lipopolysaccharide (LPS) and particular cytokines can switch on signalling pathways resulting in activation of transcription factors such as NFkB (Chapter 7) with resultant expression of proteins such as cytokines,... 

KATiYAR s K and MUKHTAR H (1997) Inhibition of phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate-caused inflammatory responses in SENCAR mouse skin by black tea polyphenols . Carcinogenesis, 18 1911-16. 

Cummins, C. L., Mangravite, L. M., Benet, L. Z., Characterizing the expression of CYP3A4 and efflux transporters (P-gp, MRP1, and MRP2) in CYP3A4-transfected Caco-2 cells after induction with sodium butyrate and the phorbol ester 12-0-tetradecanoylphorbol-13-acetate,... 

In animal studies, mirex, was tested at a dermal dose of 3.6 mg/kg 4 weeks in female CD-1 mice for tumor promoter activity and evidence of epidermal hyperplasia after initiation with 200 nmol/day 7,12-dimethyl-benz[a]anthracene (DMBA) for 1 week. Positive control mice were treated with 2 nmol/day of the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), following initiation with DMBA. A third group of mice were treated with both 3.6 mg/kg mirex and 2... 

Meyer SA, Kim TW, Moser GL, et al. 1994. Synergistic interaction between the non-phorbol ester-type promoter mirex and 12-o-tetradecanoylphorbol-13-acetate in mouse skin tumor promotion. Carcinogenesis 15(1) 47-52. 

Long-chain ester derivatives of phorbol, a tetracyclic diterpene from the seed oil of Croton tiglium L., including its most abundant representative, 12-0-tetradecanoylphorbol-13-acetate (65), are potent activators of protein kinase G (PKG) and are used as standard tumor promoters for the study of experimental carcinogenesis in animal models." ... 

Nguyen T, Rushmore TH, Pickett CB. 1994. Transcriptional regulation of a rat liver glutathione S-transferase Ya subunit gene. Analysis of the antioxidant response element and its activation by the phorbol ester 12-0-tetradecanoylphorbol-13-acetate. J Biol Chem 269 13656-13662. 

Moreover, transcription factor AP-1 and an AP-1 binding site at —355/ —349 in the DOR promoter are reportedly responsible for the induced DOR promoter activities in NG108-15 neuronal cells treated with phorbol ester O-tetradecanoylphorbol 13-acetate, while AP-2 binding of an AP-2 binding site at —157/—150 accounts for the upregulation of DOR promoter activities 48 h after treatment with forskolin [25]. This study shows that AP-2 mediates the upregulation of DOR mRNA levels by cAMP/PKA activation, while AP-1 mediates the enhancement of the DOR promoter activities by PKC activation. 

Tigliane (G5 C7 C61 C3) diterpenes include the highly irritant, toxic, co-carcinogenic, PKC activating phorbol esters from Euphorbiaceae plants. While not being activated by the parent compound phorbol, PKC is activated by plant-derived esters of phorbol, 4-deoxyphor-bol and 12-deoxyphorbol (e.g. 12-0-palmitoyl-16-hydroxy-phorbol 13-acetate, 12-deoxyphorbol 13-benzoate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate-20-acetate, sapintoxin A (4-deoxyphorbol 12-(2-methylamino)benzoate-l3-acetate) and 12-tetradecanoylphorbol 13-acetate (TPA)), as well as by synthetic phorbol esters. 

Tetradecanoylphorbol 13-acetate (TPA) and other diterpene esters from the plant family Euphorbiaceae are well-known as tumor-promotion agents [85]. Thus, inhibition of the biological effects induced by TPA has been considered as a promising strategy [68]. To date, two short-term cell-based in vitro bioassays using TPA as a tumor-promoter have been developed to evaluate the potential cancer chemopreventive activities of several lignans isolated from Hernandia species, namely, inhibition of Epstein-Barr virus early antigen activation [6] and the inhibition of the transformation of JB6 mouse epidermal cells [7]. 

Among the models of inflammation in vivo, those that involve the skin have the particular advantage that the results are immediately and continuously observable. Models of skin inflammation are numerous and varied, ranging from acute and limited to chronic and tissue-destructive. Croton oil, different phorbol esters, principally 12-tetradecanoylphorbol-13-acetate (TPA), AA and oxazolone, provide a range of skin inflammation models suitable for the evaluation of both topical and/or... 

As one might expect from its function, P450 5A1 is a highly regulated system. Dexamethasone induces P450 5A1 in human monocytes . Phorbol esters also induce P450 5A1 (e.g., 12-0-tetradecanoylphorbol-13-acetate) in human ery-throleukemia cells . Patients with systemic sclerosis showed 6-fold enhanced levels of leukocyte P450 5A1 (ref [997]). 

Palytoxin was identified as a skin tnmor two decades ago. Palytoxin is a potent tumor promoter in the monse skin carcinogenesis model. The biochemical mechanism of action of palytoxin as a tnmor promoter differs significantly from that of the prototypical phorbol ester tumor promoters. In contrast to the skin tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA), palytoxin does not activate protein kinase C or increase ornithine decarboxilase activity in the mouse skin. " There are several interesting stndies on the cellnlar mechanisms activated by palytoxin as a tumor promoter however, the biochemical mechanisms by which palytoxin-stimnlated signaling contribntes to tnmor promotion are cnrrently elncidated, and it seems that they conld depend on the experimental... 

The tumour-promoting phorbol esters, of which 12-O-tetradecanoylphorbol-13-acetate is the most potent, are non-physiological activators of protein kinase C. The same holds for Aplysiatoxin and Tele-ocidin. 

Tetradecanoylphorbol-13-acetate-induced cyclic mononucleotide phosphodiesterase activation in human blood mononuclear cells was totally abolished by ethanol, which strongly reduced phos-phatidic acid accumulation in response to the phorbol ester (Zakaroff-Girard et al. 1999). 

Tumour promoters, the most widely studied of which are the phorbol esters (Hecker 1975), have been demonstrated to stimulate superoxide anion radical production (Goldstein et al. 1979). 12-0-Tetradecanoylphorbol-13-acetate treatment of pro-Hferating murine epidermal keratinocytes (MEK) cultured in low Ca medium resulted in (i) an initial suppression of prohferation, (ii) the accelerated detachment and differentiation of detached MEKs and (iii) a suppression of catalase induction in the detached population (Reiners etal. 1990). Induction of MEK differentiation by raising the medium Ca concentration resulted in a rapid inhibition of cell division and 200 % increases in per cell catalase activities. Addition of 12-0-tetradecanoylphorbol-13-acetate immediately prior to Ca shift completely suppressed the Ca -dependent increases in activity. However, the addition of 12-0-tetradecanoyl-phorbol-13-acetate 48 h after the induction of differentiation by Ca shift had no effects on the elevated, pre-existing catalase activities. Per cell catalase activities varies in vivo with the stage of MEK differentiation. 

Two lines of murine (C57BL/5 mouse) 3-methyl-cholanthrene-induced sarcoma cells isolated from the same parent tumour responded differentially to stimulation with phorbol esters (Batchev etal. 1986). 12-0-Tetradecanoylphorbol-13-acetate stimulated the production of prostaglandin Ej in both cell lines and the rations of the amounts produced in the stimulated versus control cells were very similar. As was seen with the release of radioactivity from [ HJarachidonic acid, however, the amount of prostaglandin Ej produced in the 1.2 cells was much greater under both control and stimulated conditions than in the low-malignant variant 1.2/anti-B cells. 12-0-Tetradecanoylphorbol-13-acetate also stimulated the production of leukotriene C4 in the 1.2 cells but there was no increased production detected in the 1.2/anti-B cells. 

The inhibitory effect of antioxidants is an indirect evidence supporting a role of free radicals and reactive oxygen species in carcinogenesis. Vitamin C (Block 1992) and vitamin E (Bostick etal. 1993), which have been inversely associated with cancer incidence for a variety of sites in humans, have also been shown to inhibit tumour promotion by 12-0-tetradecanoylphorbol-13-acetate (Per-CHELLET et al. 1985, Smart et al. 1987) and non-phorbol ester-type tumour promoters (Imamoto etal. 1990, Battalora etal. 1993, Ogawa etal. 1995). Vitamin E suppressed the level of proUferat-ing cell nuclear antigens as a marker of cell proh-feration in the lungs of mice treated with urethane (Yano et al. 1997). 

Koretzky, G.A., Daniele, R.P., and Nowell, P.C. 0982). A phorbol ester 12-0-tetradecanoylphorbol-13-acetate can replace macrophages in human lymphocytes cultures stimulated with a mitogen but not with an antigen. J. Immunol. 128 1776-1780. 

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