Epidermal ornithine decarboxylase induction and mouse skin tumor promotion by quinones

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Abstract
The generation of reactive oxygen species and the subsequent development of a pro-oxidant state, such as occurs during the redox cycling of quinones, has been suggested to play a role in the tumor promotion. Moreover, we have recently shown that the relative tumor promoting activity of a series of structurally related anthrones correlated with their ability to undergo base-catalyzed oxidation. We therefore analyzed dose-response relationships for skin tumor promoting activity and the ability to induce epidermal ornithine decarboxylase (ODC) with a series of structurally related quinones. Single topical applications of 1,4-naphthoquinone and its 5-hydroxy analog (juglone) produced dose-dependent increases in epidermal ODC activity in the dose range 880–3520 nmol/mouse. These two quinones also promoted papilloma formation in female SENCAR mice initiated with 25 nmol 7,12-dimethylbenz[a]anthracene at doses capable of inducing epidermal ODC. The tumor promoting response with juglone (1760 nmol) was dependent upon the frequency of application, with the highest tumor response obtained with a three times per week application regimen. In contrast, neither 1,8-dihydroxy-9,10-anthraquinone nor 1,4-benzoquinone, at doses up to 1760 nmol/mouse, had any effect on epidermal ODC, nor did they possess tumor promoting activity after 31 weeks of promotion. Interestingly, 3-methyl-1,4-naphthoquinone (menadione), a relatively good redox cycling quinone, at a dose of 3520 nmol had only very weak ODC inducing activity and after 31 weeks of promotion (1760 nmol) did not produce a significant papilloma response in SENCAR mice. Thus, there was a good correlation between the ability of structurally related quinones to induce epidermal ODC and their ability to behave as tumor promoters. In contrast, a relationship between quinone redox cycling and tumor promotion was not readily apparent. Finally, under optimal promoting conditions, juglone was very effective at supporting the conversion of papillomas to carcinomas (carcinoma/papilloma ratio of 0.35). In addition, histological examination of all tumors produced during promotion with juglone revealed the presence of both kerathoacanthomas and sebaceous squamous cell carcinomas. These latter tumors, not found in the anthrone group, may be indicative of a potentially unique site and/or mechanism of action for this class of compounds.