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Xanthine compounds (caffeine analogues) inhibit cell transformation and stimulate apoptosis in JB6 Cl41 mouse epidermal cells. We studied the structure-activity relationships of three groups of xanthines, for their differential effect on malignant cell transformation and apoptosis in JB6 cells. Japanese scientists previously performed similar structure-activity relationship studies for the same three groups of xanthines to determine their role in the inhibition of cyclic AMP-phosphodiesterase (cAMP-PDE). cAMP-PDE is known to be responsible for the hydrolysis of the second messenger, cyclic AMP (cAMP), which plays a fundamental role in the transduction of the intracellular signals and its deregulation may have a role in carcinogenesis. Controversial results regarding the modulation of apoptosis and cell transformation by cAMP are reported. We used the results of the Japanese study and our study to determine a possible relationship of cAMP-PDE and the inhibition of cell transformation and stimulation of apoptosis induced by xanthines. We observed a significant correlation between the cell transformation and cAMP-PDE by the 1-substituted 3-H-7H-xanthines (Spearman = - 0.97; p=0.005; n=5). Generally, cAMP-PDE functions to degrade cAMP and therefore, inhibition of cAMP-PDE results in increased levels of cAMP. Xanthines increase the level of intracellular cAMP through the inhibition of cAMP-PDE. Our data show that relative increases in the inhibition of cell transformation are related to a weaker inhibition of cAMP-PDE by the xanthines. We found similar correlations between early apoptosis and inhibition of cAMP-PDE (Spearman = 0.70; p=0.036; n=9) within 1-substituted 7-H- and 7-methyl-3-propylxanthines. Also we found a significant correlation between inhibition of cAMP-PDE and late apoptosis/necrosis (Spearman = 0.39; p=0.049; n=25). This implies that early apoptosis or late apoptosis/necrosis increases as the inhibition of cAMP-PDE decreases resulting in lesser increases in cAMP. 1-Hexyl-3-propyl-7-metylxanthine (Xt 79) was most effective at inhibiting cell transformation within the 1,3,7-trialkylxanthine group of caffeine analogues. We studied the effect of Xt 79 on EGF-stimulated JB6 Cl 41 cells by western blot and the results indicated that Xt 79 inhibits expression of PKA. PKA is known to stimulate transcription and inhibit apoptosis.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]