TPA-type tumor promoters

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

Inhibition of EGF binding by palytoxin could be due to a decrease in receptor affinity, as in the case of TPA-type tumor promoters, and/or a decrease in receptor number. In Swiss 3T3 cells there are two classes of EGF receptors. The dissociation constants for the two EGF receptor classes were determined to be approximately 2 X 10 M and 2 x 10" M, corresponding to approximately 1 x 10 and 1 X 10 receptor molecules per cell, respectively (33). Scatchard analysis revealed that treatment of Swiss 3T3 cells with palytoxin, like PDBu, caused an apparent loss in high-affinity binding (Figure 2). However, in contrast to PDBu, palytoxin also caused a significant (approximately 50%) loss of low affinity EGF binding. 

Non-TPA Type Tumor Promoters Palytoxin and Okadaic Acid Class... 

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. 

In addition to okadaic acid, dinophysistoxin-1 (i.e., 35-methylokadaic acid), 7-0-palmitoyl-okadaic acid, and pectenotoxin 2 are reported to be diarrhetic toxins from shellfish 34). Application of 1 xg of dinophysistoxin-1 to mouse ear caused as strong irritation as the same dose of okadaic acid. Interestingly, the potencies of these compounds in the irritant test on mouse ear correlated well with their potencies as diarrhetic shellfish poisons. Dinophysistoxin-1 induced ODC activity as strongly as okadaic acid. Recently, we found that dinophysistoxin-1 is also a new non-TPA type tumor promoter with as high activity as okadaic acid 35). 

We have shown that TPA-type tumor promoters, such as lyngbyatoxin A and aplysi-atoxins exert tumor promoting activities on mouse skin through different mechanisms from those of non-TPA type tumor promoters such as palytoxin, okadaic acid, and dinophysistoxin-1. 

As discussed in the previous sections, a number of triterpenoids with great structural diversity have antitumor-promoting activities. In contrast, 28-deacetylbelamcandal (288), a spiroiridal-type triterpenoid, has recently been reported to possess tumor promoting activity [92]. Compound 288, which stimulated differentiation of human promyelocytic leukemia (HL-60) cells (a fast method for screening TPA-type tumor promoters),... 

Kuroki, D.W, Bignami, G.S., and Wattenberg, E.V 1996. Activation of stress-activator protein kinase/c-Jun N-terminal kinase by the non-TPA-type tumor promoter palytoxin. Cancer Res 56, 637-644. 

Ohuchi K, Sugawara T, Watanabe M (Other Authors ). (1988). Analysis of the stimulative effect of thapsigargin, a non-TPA-type tumor promoter, on arachidonic acid metahtdism in rat peritonial macrophages. Br. J. Pharmacol. 94 917-923. 

With regard to other effects of palytoxin on metabolism, it is interesting to mention that palytoxin has been reported to stimulate both metabolism of arachidonic acid and prostaglandin production [65]. These properties are thought to be related with palytoxin s tumor-promoting activity, as palytoxin is a known non-TPA-type tumor promoter [66],... 

Ohuchi, K., et al.. Stimulation of prostaglandin Ej production by 12-O-tetradecanoylphorbol 13-acetate (TPA)-type and non-TPA-type tumor promoters in macrophages and its inhibition by cycloheximide, Biochim. Biophys. Acta, 834, 42, 1985. 

Kano, S., et al.. Stimulation of superoxide anion formation by the non-TPA type tumor promoters palytoxin and thapsigargin in porcine and human neutrophils, Biochem. Biophys. Res. Comm., 143, 672, 1987. 

Mirex is a non-TPA type tumor promoter (12,13). Female CD-I initiated with a single dose of 200 nmol of DMBA and promoted with 0.1 pmol of mirex 3 times a week for 18 weeks developed an average of 11.5 skin tumors per mouse, and 80% of mice had skin tumors. Topical application of 10 pmol of DBM with 0.1 pmol of mirex 3 times a week for 18 weeks inhibited the mirex-induced average number of skin tumors per mouse by 62.6%, and percentage of mice bearing with tumors was decreased by 12.5% (Table III). The results indicate that DBM inhibits both TPA- and a non-TPA type tumor promotion in mouse skin (Tables II III). 

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