Promotion, tumor phorbol esters

Palytoxin is a relatively large (MW 2681), hydrophilic compound (7, 2), unlike the prototypical TPA-type tumor promoters, the phorbol esters. Although palytoxin... 

Hennings, H., Blumberg, P. M., Pettit, G. R., Herald, C. L., Shores, R., and Yuspa, S. H., Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin, Carcinogenesis, 8, 1343, 1987. 

The spatial and steric requirements for high affinity binding to protein kinase C (PKC), a macromolecule that has not yet been crystallized, were determined. Protein kinase C plays a critical role in cellular signal transduction and is in part responsible for cell differentiation. PKC was identified as the macromolecular target for the potent tumor-promoting phorbol esters (25). The natural agonists for PKC are diacylglycerols (DAG) (26). The arrows denote possible sites of interaction. 

In contrast to the TPA-type tumor promoters, palytoxin, thapsigargin, and okadaic acid are classified as non-TPA type tumor promoters, which do not bind to phorbol ester receptors, or activate protein kinase C in vitro (Table II) (6,25-27). In this chapter, thapsigargin is not discussed, because it is derived from terrestrial plants. 

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. 

The majority of these members are a receptor for phorbol esters, the tumor-promoting products obtained from croton oil. One of them, 12-O-tctradccanoylphorbol- 13-acetate (TPA), is a potent... 

Although benz(a)anthracene (BA) is generally considered noncarcino-genic (27), it is a weak tumor initiator when administered with a phorbol ester promoter (28). More importantly, BA is a convenient model for the highly potent carcinogenic PAH 7,12-dimethylbenz(a)-anthracene and 3-methylcholanthrene (27), both of which are BA derivatives but which offer more serious synthetic problems. 

The phorbol esters are useful for studying the function of PKC since they mimic the stimulatory effects of DAG on the enzyme. These tumor-promoting plant products and their synthetic derivatives are able to penetrate intact cells. Many inferences regarding the intracellular actions of PKC are based on results of studies on whole-cell preparations with the phorbol esters. These substances, like DAG, may produce feedback inhibition of signal transduction at a number of metabolic levels. Results of experiments using phorbol esters in whole cells are thus often complex and must be interpreted cautiously. Notwithstanding this consideration, based upon... 

Under basal conditions, PKC is predominantly a cytoplasmic protein. Upon activation by Ca2+ or DAG, the enzyme associates with the plasma membrane, the site of many of its known physiological substrates, including receptors and ion channels. In fact, the translocation of PKC from the cytoplasm to the membrane has long been used as an experimental measure of enzyme activation. Such translocation has often been assayed by phorbol ester binding phorbol esters are tumor-promoting agents that selectively bind to and activate PKC. The molecular basis of the translocation of PKC from the cytoplasm to the plasma membrane has been solved. Subsequent to activation, PKC binds with high affinity to a series of membrane-associated proteins, termed receptors for... 

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... 

As indicated above in the section on "Genotoxic Effects", it is likely that mirex and chlordecone are tumor promoters and not tumor initiators. Initiators irreversibly alter DNA by a mutation, chromosomal aberration, or other alteration. Promoters act by facilitating the proliferation of previously initiated preneoplastic cells. One of the mechanisms for promotion is believed to involve suppression of inhibitory proliferative control through inhibition of gap-junctional-mediated intercellular communication as well as enzyme induction (Trosko et al. 1983). The results of studies to evaluate the promotional activity potential of mirex in mice indicate that mirex is a mouse skin cancer promoter but exerts this toxicity through a hitherto unknown mechanism that is different from that of phorbol esters, such as TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). Unlike initiation, promotion is a reversible process to a point. This implies, at least in theory, that there may be justification for setting NOAELs for promoters. 

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. 

Phorbol esters are described to stimulate apical transcytosis probably via protein kinase C. These effects can be achieved by incubating cells with the tumor promoter PM A [1 pM (to 2pM)] for 30 minutes (to 60 minutes) (107,108). The total drug exposure time to about one hour because PMA shows an influence on tight junction permeability and thereby changes the transepithelial resistance. 

Tumor promotion is preferential proliferation of a cell damaged by transformation, it is a very slow process that can take many years. Certain substances are able to strongly accelerate it—e.g., phorbol esters. These occur in plants (e. g.. Euphorbia species) and act as activators of protein kinase C (see p. 386). 

Kazanietz MG, CalocaMJ, Eroles P, et al, Pharmacology of the receptors for the phorbol ester tumor promoters Multiple receptors with different biochemical properties, Biochem Pharmacol 6Q A 7— A2A, 2000. 

To date the evidence seems to favor the binding of tumor promoter to phospholipid in the cell membrane. Specific binding of [3h]TPA to mouse epidermal particulate matter is susceptible to phospholipases C and A2, less susceptible to protease, and completely resistant to glycosidase (32). Photoaffinity labelling studies with [20-3h]-phorbol 12-p-azidobenzoate 13-benzoate indicates that the irreversible binding of this photolabile phorbol ester to mouse brain membrane is predominantly to the phospholipid (specifically phosphatidylethanolamine and phosphatidylserine) portion rather than to the protein portion (33). 

Technical-grade CMME (contaminated with BCME), on subcutaneous injection in mice, has produced local sarcomas. Dermal application of mice, followed by a phorbol ester promoter, resulted in an apparent excess of skin papillomas and carcinomas. Inhalation studies in mice showed an equivocally increased occurrence of lung tumors compared with unexposed controls. ... 

However, in contrast to phorbol esters, bryostatins do not act as tumor promoters. In many systems bryostatin 1 induced only a subset of the responses to TPA and sometimes blocked those which it did not induce (Blumberg, 1991). 

Ahmed S, Lee J, Kozma R, Best A, Monfries C, Lim LA (1993) A novel functional target for tumor-promoting phorbol esters and lysophosphatidic acid. The p21rac-GTPase activating protein n-chimaerin. J Biol Chem 268 10709-10712... 

Caloca MJ, Fernandez N, Lewin NE, Ching D, Modali R, Blumberg PM, Kazanietz MG (1997) Beta2>chimaerin is a high affinity receptor for the phorbol ester tumor promoters. J Biol Chem 272 26488-26496... 

Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y (1982) Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 257 7847-7851... 

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