Abstract
Sarcophine derivatives have been suggested to be chemopreventive in nature. One of its derivatives, Sarcotriol (ST), was investigated to study the skin cancer chemopreventive effects in female CD-1 mice. Three groups (control, promotion, initiation) of 30 female CD-1 mice each were taken. Carcinogenesis was initiated with 7, 12-dimethylbenz (a) anthracene (DMBA) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). One hour before treating with DMBA (200 nmol/100 μl acetone), control and promotion groups were treated with acetone (100 μl) and initiation group with ST (30μg/100μl of acetone). Beginning one week after initiation with DMBA, control and initiation groups were treated with acetone and promotion group with ST (30μg/100μl of acetone), one hour before treating with TPA (5 nmol/100 μl acetone). This was carried out twice a week for the next 20 weeks. The effects of ST on 3H-thymidine incorporation in epidermal DNA, the possible role of apoptotic proteins and COX-2 involved in the prevention of skin tumor development of CD-1 mice were investigated. Tumor incidence and multiplicity was found to be 100%, 73%, 100% and 8.2, 4.8, 9.7 in control, promotion and initiation groups respectively. ST treatment resulted in a significant (P < 0.05) inhibition in the incorporation of 3H-thymidine in epidermal DNA. The promotion group showed higher levels of caspase-3, -8 and –9 compared to the control. COX-2 expression was significantly lower (P < 0.05) in the promotion group as compared to the control. No significant difference in caspase-3, -8, -9 and COX-2 levels were observed in the initiation group compared to control. Together, this study confirms the chemopreventive effects of ST, and for the first time identifies the stage of carcinogenesis at which ST exerts its chemopreventive effect, and elucidates the mechanism possibly by inducing apoptosis and decreasing the COX-2 levels, contributing to its overall cancer chemopreventive effects in the mouse skin cancer model.
Highlights
Skin cancer is the most common type of cancer, accounting to nearly half of all cancers in United States [1]
We have examined the effect of ST on dimethylbenz (a) anthracene (DMBA)-initiated and TPA. Promoters like 12-Otetradecanoylphorbol-13-acetate (TPA)-promoted tumorigenesis in a two-stage skin carcinogenesis model
The results from this investigation indicated that ST inhibited skin papilloma development as reflected in tumor incidence, to a lesser extent, and tumor multiplicity only in the promotion group which indicates that ST was effective only during the promotion phase of DMBA and TPA protocol
Summary
Skin cancer is the most common type of cancer, accounting to nearly half of all cancers in United States [1]. Chemical and UVB radiation-induced carcinogenesis in murine skin and possibly human skin is a stepwise process of at least three distinct stages: initiation, promotion, and progression [9]. One of them is sacophytol A, an oxygenated cembrene-type diterpenoid isolated from the Okinawan soft coral Sarcophyton glaucum, which has been shown to have significant inhibitory activity against various classes of tumor promoters and hydrogen peroxide formation by TPA activated human polymorphonuclear leukocytes [12]. In our previous work [1418], we have reported a new serious of sarcophine derivatives that displayed a potent chemopreventive activity against skin cancer, one of which is sarcotriol (ST). The purpose of the present investigation is to deterime what stage of carcinogenesis ST inhibits during the study of its chemopreventive effects on DMBA-initiated and TPA-promoted skin papillomas in CD-1 mice. To elucidate the possible mechanism of action of ST, 3H-thymidine incorporation in epidermal DNA, Caspase-3, -8, -9 and COX-2 expression were determined
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