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), neoabietic acid (3), dehydroabietic acid (4), and podocarpic acid (8), as well as resin acid derivatives 8β,9α,13α-H-tetrahydroabietic acid (5), 8α,9α,13α-H-tetrahydroabietic acid (6), 13α-H-Δ(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 (IC(50): 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 μmol) along with DMBA (100 μg)/TPA (1 μg) 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.
Tanaka
Reiko
R
Department of Medicinal Chemistry, Osaka University of Pharmaceutical Science, Takatsuki, Osaka, Japan. tanakar@gly.oups.ac.jp
Tokuda
Harukuni
H
Ezaki
Yoichiro
Y
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000956:Antigens, Viral / Q000378:metabolism; D002264:Carboxylic Acids / Q000494:pharmacology; D015197:Carcinogenicity Tests; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D010212:Papilloma / Q000139:chemically induced / Q000517:prevention & control / Q000821:virology; D010616:Phenanthrenes / Q000494:pharmacology; D028223:Pinus / Q000737:chemistry*; D012116:Resins, Plant / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000517:prevention & control* / Q000821:virology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D016588:Anticarcinogenic Agents; D000956:Antigens, Viral; D002264:Carboxylic Acids; C033305:Epstein-Barr virus early antigen; D010616:Phenanthrenes; D012116:Resins, Plant; C115138:isopimaric acid; D015127:9,10-Dimethyl-1,2-benzanthracene; C013893:rosin; D013755:Tetradecanoylphorbol Acetate