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Rogozin, E. A.,Lee, K. W.,Kang, N. J.,Yu, H.,Nomura, M.,Miyamoto, K.-I.,Conney, A. H.,Bode, A. M.,Dong, Z. Oxford University Press 2008 Carcinogenesis Vol.29 No.6
<P>Some xanthine analogues, including 1,3,7-trimethylxanthine (caffeine) and 1,3-dimethylxanthine (theophylline), have been shown to exert anticancer activities in both cell culture and animal models. The present study focused on the relationship of structure and activity of 50 different caffeine analogues in preventing epidermal growth factor (EGF)-induced malignant transformation of mouse epidermal JB6 promotion-sensitive (P+) Cl41 (JB6 P+) cells. Results indicated that the inhibition of cell transformation by the 1,3,7-trialkylxanthines depends on the number of carbons at the alkyl groups R1 and R3, but not R7. Notably, 1-ethyl-3-hexylxanthine (xanthine 70) was the most effective compound for inhibiting EGF-induced neoplastic transformation among the 50 xanthine analogues tested. The 50% inhibition of cell transformation (ICT(50)) value for xanthine 70 was 48- or 75-fold less than the ICT(50) value of caffeine or theophylline, respectively. Further study revealed that xanthine 70 (5-40 muM) dose dependently inhibited EGF-induced transactivation of activator protein 1 (AP-1), whereas theophylline or caffeine (up to 500 muM) had no effect on AP-1 activity. In addition, xanthine 70 (10 muM) inhibited 12-O-tetradecanoylphorbol-13-acetate- or H-Ras-induced neoplastic transformation in JB6 P+ cells by 78.2 or 62.0%, respectively. Collectively, these results indicated that the number of carbons at R1 and R3 is important for the antitumor-promoting activity of the trialkylxanthines and xanthine 70 might be a promising anticancer agent.</P>
Cocoa procyanidins suppress transformation by inhibiting mitogen-activated protein kinase kinase.
Kang, Nam Joo,Lee, Ki Won,Lee, Dong Eun,Rogozin, Evgeny A,Bode, Ann M,Lee, Hyong Joo,Dong, Zigang American Society for Biochemistry and Molecular Bi 2008 The Journal of biological chemistry Vol.283 No.30
<P>Cocoa was shown to inhibit chemically induced carcinogenesis in animals and exert antioxidant activity in humans. However, the molecular mechanisms of the chemopreventive potential of cocoa and its active ingredient(s) remain unknown. Here we report that cocoa procyanidins inhibit neoplastic cell transformation by suppressing the kinase activity of mitogen-activated protein kinase kinase (MEK). A cocoa procyanidin fraction (CPF) and procyanidin B2 at 5 mug/ml and 40 mum, respectively, inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ mouse epidermal (JB6 P+) cells by 47 and 93%, respectively. The TPA-induced promoter activity and expression of cyclooxygenase-2, which is involved in tumor promotion and inflammation, were dose-dependently inhibited by CPF or procyanidin B2. The activation of activator protein-1 and nuclear factor-kappaB induced by TPA was also attenuated by CPF or procyanidin B2. The TPA-induced phosphorylation of MEK, extracellular signal-regulated kinase, and p90 ribosomal s6 kinase was suppressed by CPF or procyanidin B2. In vitro and ex vivo kinase assay data demonstrated that CPF or procyanidin B2 inhibited the kinase activity of MEK1 and directly bound with MEK1. CPF or procyanidin B2 suppressed JB6 P+ cell transformation induced by epidermal growth factor or H-Ras, both of which are known to be involved in MEK/ERK signal activation. In contrast, theobromine (up to 80 mum) had no effect on TPA-induced transformation, cyclooxygenase-2 expression, the transactivation of activator protein-1 or nuclear factor-kappaB, or MEK. Notably, procyanidin B2 exerted stronger inhibitory effects compared with PD098059 (a well known pharmacological inhibitor of MEK) on MEK1 activity and neoplastic cell transformation.</P>