Tumor promoting activities, phorbol

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... 

A property of the protein kinase C enzyme family that is highly valuable for their identification and characterization is their activation by tumor promoters such as phorbol esters (Fig. 7.7). Protein kinase C binds to the tumor promoter, tetradecanoyl phorbol acetate (TPA), with high affinity and is activated by this binding. The specific activation of protein kinase C by phorbol esters is an important tool to demonstrate their involvement in signal transduction pathways. By external addition of TPA, it is possible to use cellular model systems to test which biological responses of a signal transduction pathway involve, and are controlled by, protein kinase C. 

Induction of epidermal ODC is a characteristic biochemical alteration elicited by TPA and may be representative of the effects of phorbol esters with strong tumor promoting activity [81]. A single application of TPA (5 pg) resulted in a substantial and transient increase of epidermal ODC activity in mice with a peak at about 4 h after TPA treatment, and the induction was potently inhibited by treatment (5 pM) of the mouse skin with sitosterol (33, 65% inhibition) and three lupane type triterpenoids betulin (255 79%), betulinic acid (257 89%), and lupeol (264,96%) [30]. The inhibitory effect on TPA-induced ODC activity was further reported for ursolic acid (210 45% inhibition at 2.0 pM/5nM of TPA) [31]. 

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. 

Nishino, H. Okuyama, T. Takata, M. Shibata, S. Tokuda, H. Takayasu, J. Hasegawa, T. Nishino, A. Ueyama, H. Iwashima, A. Studies on the anti-tumor-promoting activity of naturally occurring substances IV. Pd-H [(+)anomalin, (- -)praeruptorin B], a seselin-type coumarin, inhibits the promotion of skin tumor formation by 12-O-tetradecanoyl-phorbol-13-acetate in 7,12-dimethylbenz[a]anthracene-initiated mice. Carcinogenesis (London), 1990, 11 1557-1561. 

Recent developments in cellular biology have demonstrated the important role of mitogenic signal transduction in controlling the tumor proliferation. The induction of ornithine decarboxylase (ODC), PKC, protein kinase activities, and oxidative stress by the phorbol ester, TPA, is believed to be closely related to the tumor promotion activity of this compound. Topical application of green tea polyphenols to mouse skin was found to inhibit TPA-caused induction of ODC activity in a dose-dependent manner. Our studies demonstrated that EGCG and TF-3 inhibited TPA-induced transformation, PKC activation, and AP-1 binding activities in mouse fibroblast cells. ... 

Also the relative tumor-promoting activities [nrtpa] of phorbol esters (41) have been correlated with their lipophilicity (eq. 177) [780]. 

Nakao, M., Hasegawa, G., Yasuhara, T., Ishihara, Y, 2015. Degradation of Jatropha curcas phorbol esters derived from Jatropha oil cake and their tumor-promoting activity. Ecotoxicol. Environ. Saf. 114,357-364. 

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. 

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... 

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. 

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). 

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." ... 

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... 

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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