Suppression of tumor promoter-induced oxidative events and DNA damage in vivo by sarcophytol A: a possible mechanism of antipromotion.
Sarcophytol A (Sarp A), a nontoxic compound isolated from marine soft coral, inhibits the in vivo effects of tumor promoters. However, the mechanism of its action is unknown. Our studies show that Sarp A suppresses oxidant formation and DNA oxidation in the epidermis of SENCAR mice exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA). In the short-term experiments, mice were topically pretreated with different doses of Sarp A before 6.5 nmol TPA, and the same treatment was repeated 20 h later. Sarp A significantly decreased the TPA-induced infiltration of neutrophils, the levels of myeloperoxidase in the dermis, and the formation of H2O2, cis-thymidine glycol, 8-hydroxyl-2'-deoxyguanosine, and 5-hydroxymethyl-2'-deoxyuridine in the epidermis. In the long-term studies, repeated TPA applications (3.2 nmol twice a week for 16 weeks) increased cis-thymidine glycol 2.7-fold, 5-hydroxymethyl-2'-deoxyuridine 3.4-fold, and 8-hydroxyl-2'-deoxyguanosine 3.3-fold in epidermal DNA over the basal levels. Application of 350 nmol Sarp A before each TPA treatment significantly decreased the formation of oxidized DNA bases even below those present in the control mouse skin. Histological examination showed that Sarp A also alleviated the TPA-induced inflammatory response and infiltration of phagocytes. Thus, it is possible that suppression of tumor promotion by Sarp A is due (at least in part) to its inhibitory effects on tumor promoter-mediated migration and activation of phagocytes, oxidant formation, and DNA base oxidation.
Wei
H
H
Department of Environmental Medicine, New York University Medical Center, New York 10016-6451.
Frenkel
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D004247:DNA / Q000187:drug effects* / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006965:Hyperplasia / Q000139:chemically induced; D051379:Mice; D009504:Neutrophils / Q000187:drug effects*; D010084:Oxidation-Reduction; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate
D000970:Antineoplastic Agents; D004224:Diterpenes; C058761:sarcophytol A; D004247:DNA; D006861:Hydrogen Peroxide; D013755:Tetradecanoylphorbol Acetate