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.
Nakamura
Y
Y
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Japan.
Kawamoto
N
N
Ohto
Y
Y
Torikai
K
K
Murakami
A
A
Ohigashi
H
H
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