A diacetylenic spiroketal enol ether epoxide from Artemisia lactiflora inhibits 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion

Y Nakamura, PhD,a, A Murakami, PhD,b, H Ohigashi, PhD,c.

aNagoya University Graduate School of Bioagricultural Sciences, Nagoya, Aichi Japan, bFaculty of Biology-Oriented Science and Technology, Kinki University, Iwade-Uchita, Wakayama Japan, cGraduate School of Agriculture, Kyoto University, Kyoto Japan.

[AIM] Six acetylene compounds including AL-1 (3,4-epoxy-(2,4-hexadiynyliden)-1,6-dioxaspiro[4,5]decane and its derivatives) have recently been isolated from the leaves of Artemisia lactiflora (Compositae), an edible plant of Thailand, and identified as inhibitors of superoxide generation in differentiated HL-60 cells. In the present study, the inhibitory effect of the diacetylene epoxide, AL-1, on tumor promoter-induced oxidative stress as well as tumor promotion in ICR mouse skin was investigated. [METHODS] Skin carcinogensis experiment was performed by the representative protocol using 12-O-tetradecanoylphorbol-13-acetate (TPA) and 7,12-dimethylbenz[a]anthracene in ICR mouse skin. Hydrogen peroxide generation in mouse skin induced by double TPA application was estimated by a horseradish peroxidase-phenol red method. [RESULTS] Pretreatments of AL-1 (810 nmol) significantly suppressed double TPA application-induced hydrogen peroxide generation. Pretreatment of AL-1 only before the second TPA treatment was sufficient to inhibit, while only with the first treatment was not. These results suggested that AL-1 is a specific inhibitor of leukocyte activation. In a two-stage skin carcinogenesis experiment, topical application of AL-1 (at 160 nmol) significantly reduced tumor incidence, the numbers of tumors per mouse, and edema formation. [CONCLUSIONS] These results suggest that an inhibitor of superoxide generation is an effective chemopreventer of mouse skin carcinogenesis by their antioxidant property.

KEY WORDS: cancer chemoprevention, superoxide, antioxidant, leukocyte.

For more information, contact

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Dietary Influences.