Cancer chemopreventive activity of rosin constituents of Pinus spez. and their derivatives in two-stage mouse skin carcinogenesis test

Natural resin acids present in rosin of Pinus spez., including isopimaric acid (1), mercusic acid (2), neoabletic acid (3), dehydroabietic acid (4), and podocarpic acid (8), as well as resin acid derivatives 8 beta,9 alpha,13 alpha-H-tetrahydroabletic acid (5), 8 alpha,9 alpha,13 alpha-H-tetrahydroabietic acid (6), 13 alpha-H-Delta(8)-dihydroabietic acid (7), maleopimaric acid (9), and fumaropimaric acid (10), were studied for their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Compounds 1, 3, 4, 7, and 10 (IC50: 352, 330, 311, 340, and 349, respectively) exhibited strong inhibitory effects compared to the other compounds. Among these, 1, 4, and 7 were selected to examine their effects on in vivo two-stage mouse skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) as initiator and TPA as promoter. Treatment with compounds 4 and 7 (85 nmol) along with DMBA/TPA inhibited papilloma formation up to week 8 and the percentage of papilloma bearers in these two groups was approximately 80% at week 20. The average number of papillomas formed per mouse was 4.4 and 4.2 even at week 20 (p > 0.05). Compounds 4 and 7 exhibited high activity in the in vivo anti-tumor-promoting test. In addition, rosin was examined in vivo for its chemopreventive effect. Treatment with rosin (50 mu mol) along with DMBA (100 mu g)/TPA (1 mu g) inhibited papilloma formation up to week 8 and the percentage of papilloma bearers in this group was less than 80% at week 20. The average number of papillomas formed per mouse in the rosin-treated group was 3.8 even at week 20 (p > 0.05). The in vivo two-stage mouse skin carcinogenesis test revealed that rosin possessed a pronounced anticarcinogenetic effect, and its high activity is due to the synergism of the diterpenes contained in it. (C) 2008 Elsevier GmbH. All rights reserved.