Phorbol ester tumour promotion

IP3 acts as the second messenger for Ca2+ mobilisation from the endoplasmic reticulum while DAG stimulates the Ca2+ sensitive protein kinase C (which modulates EGF receptor) and activates the plasma membrane Na+/H+ exchange carrier. In this function DAG is mimicked by phorbol esters which have a tumour promoting function. The effect of stimulating Na+/H+ exchange is to increase the intracellular pH and K+ concentration, conditions which are necessary to induce or maintain the proliferative response in quiescent cells (Rozengurt, 1986 Wakelam, 1989). 

F. Rippmann, Quant. Struct.-Act. Relat., 9,1 (1990). Hydrophobicity and Tumour Promoting Activity of Phorbol Esters. 

The bryostatins are naturally occurring macrocyclic lactones isolated from marine bryozoa that have antineoplastic activity. These macrolactones exhibit high affinities for PKC isoenzymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. They do not act as tumour promoters. The bryostatins are a class of PKC activators that induce only a subset of the typical phorbol ester responses... 

The phorbol derivative (131) has been isolated from Croton rhamnifolius A group of tumour-promoting esters, based on 12-desoxyphorbol, have been... 

The structure of pendolmycin is closely related to the structures of tumour-promoting teleocidin and lyngbiatoxin (Fig. 15). Like tumour promoters pendolmycin binds to the phorbol ester receptor, and is an activator of protein kinase C. Pendolmycin suppresses EGF receptor tyrosine kinase by stimulating phosphorylation of EGF receptor, resulting in inhibition of EGF-induced PI turnover in A431 cells (28). Thus, actually. 

Beckman et al (1994) used normal-phase HPLC of constituent hydroxy fatty acids followed by GC/MS analysis to reveal that the oxidized GPL in the skin of CDi mice, following application of the tumour-promoter phorbol esters, were oxidized derivatives of linoleic acid, including 9- and 13-hydroxyoctadecadienoic acids (9- and 13-HODE). Sodium borohydride reduction increased product yield by approximately 50%, suggesting the additional presence of GPL hydroperoxides in the oxidized lipids. 

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. 

Phorbol ester-induced ornithine decarboxylase (EC 4.1.1.17) activity associated with tumour promotion (O Brien 1976) was inhibited by deguelin, tephrosin, (-)-13a-hydroxytephrosin, and (-)-13a-hydroxydeguelin, four rotenoids obtained from the African legume Mundulea sericea (Gerhauser et al. 1995). 17 nmole of retinoic add, when applied 1 h before treatment of mouse skin with 5 nmole of... 

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. 

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). 

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