A diacetylenic spiroketal enol ether epoxide, AL-1, from Artemisia lactiflora inhibits 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion possibly by suppression of oxidative stress.
The inhibitory effects of the diacetylenic spiroketal enol ether epoxide AL-1 from Artemisia lactiflora on a variety of tumor promoter-induced biological responses such as oxidative stress as well as tumor promotion in ICR mouse skin were investigated. AL-1 inhibited TPA-induced intracellular peroxide formation in differentiated HL-60 cells, suggesting that this suppression might be attributable to the inhibition of O2- generation. In a double TPA application system in mouse skin, double pretreatments of AL-1 (810 nmol) significantly suppressed double TPA application-induced H2O2 generation. Pretreatment of AL-1 only before the second TPA treatment was sufficient to inhibit, while only with first treatment was not. From these results we concluded that AL-1 is a specific inhibitor of the activation phase in H2O2 production induced by double TPA treatments. In addition, AL-1 strongly inhibited tumor promoter-induced Epstein-Barr virus (EBV) activation in Raji cells (IC50 = 0.5 microM), which was comparable to or even stronger than that of curcumin, a well-known antioxidative chemopreventer from turmeric. In a two-stage carcinogenesis experiment with TPA (topical application at 1.6 nmol) and 7,12-dimethylbenz[a]anthracene (DMBA, at 0.19 micromol) in ICR mouse skin, topical application of AL-1 (at 160 nmol) significantly reduced tumor incidence, the numbers of tumors per mouse, and edema formation by 58% (P < 0.01 in t-test), 20% (P < 0.005 in chi2-test) and 42% (P < 0.01), respectively. These results together indicate that an inhibitor of O2 generation is an effective chemopreventer of mouse skin carcinogenesis by their antioxidative property.
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Japan.
Y
Y
Nakamura
N
N
Kawamoto
Y
Y
Ohto
K
K
Torikai
A
A
Murakami
H
H
Ohigashi
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D015197:Carcinogenicity Tests; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018922:HL-60 Cells; D004854:Herpesvirus 4, Human / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D018384:Oxidative Stress / Q000187:drug effects*; D011714:Pyrans / Q000494:pharmacology / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D013755:Tetradecanoylphorbol Acetate; D014407:Tumor Cells, Cultured; D014775:Virus Activation / Q000187:drug effects
C120620:Al 1 spiroketal enol ether epoxide; D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D011714:Pyrans; D013141:Spiro Compounds; D015127:9,10-Dimethyl-1,2-benzanthracene; D006861:Hydrogen Peroxide; D013755:Tetradecanoylphorbol Acetate