Synergistic Effects of Combined Phytochemicals and Skin Cancer Prevention in SENCAR Mice

Abstract

The purpose of our study was to determine the inhibitory effect of combined phytochemicals on chemically induced murine skin tumorigenesis. Our hypothesis was that concurrent topical and dietary treatment with selected compounds would lead to more efficient prevention of skin cancer. We tested ellagic acid and calcium D-glucarate as components of diets, while resveratrol was applied topically; grape seed extract was applied topically or in the diet. The 4-week inflammatory-hyperplasia assay based on the 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis model in SENCAR mice was used. We have found that all the selected combinations caused a marked decrease of epidermal thickness compared with the DMBA-treated group and also with groups treated with a single compound and DMBA. All combinations of resveratrol with other compounds showed a synergistic effect on hyperplasia and Ha-ras mutations. Skin tissue of mice receiving the combinations showed decreased cell proliferation and Bcl2 expression; decreased p21, a regulator of cell cycle; and decreased marker of inflammation cyclooxygenase-2. All the selected combinations diminished the DMBA-induced mRNA expression of the CYP1B1 level, and also caused a marked decrease of proto-oncogenes c-jun and c-fos, components of transcription factor activator protein. In conclusion, all combinations showed either additive or synergistic effects and their joint actions allowed for decreasing the doses of the compounds. Especially, resveratrol combinations with ellagic acid, grape seed extract, and other phytochemicals are very potent inhibitors of skin tumorgenesis, based on the suppression of epidermal hyperplasia as well as on the modulation of intermediate biomarkers of cell proliferation, cell survival, inflammation, oncogene mutation, and apoptosis.Cancer Prev Res; 3(2); 170-8. ©2010 AACR.

Safety Assessment of Vitis vinifera (Grape)-Derived Ingredients as Used in Cosmetics

“…64,74,[77][78][79][80][81][82][83] Seed polyphenols and extracts in particular were shown to inhibit 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted tumors in mouse skin; both dermal application and dietary administration had significant inhibitory activity. 74,79,80,82,84 Dietary grape seed extract also inhibited UVinitiated, UV-promoted, or UV-initiated and promoted skin tumors in hairless mice, 64 and it inhibited the formation of azoxymethane (AOM)-induced aberrant crypt foci (ACF) in the intestines of rats. 83 Some of the studies summarized in Table 11 examined the effect of applying DMBA to mice and then later either treating the animals topically or in the diet with grape seed extract without TPA.…”

Grape seed and skin extract protects against acute chemotherapy toxicity induced by doxorubicin in rat red blood cells and plasma

“…GSSE also protects against hepatic ischemia-reperfusion injury (Sehirli et al, 2008), biliary obstruction (Dulundu et al, 2007), and azathioprineinduced hepatotoxicity in rats (El-Ashmawy et al, 2010). More specifically, resveratrol is multi-organ protective owing to its anti-oxidant (Kelen and Tepe, 2007) and anti-inflammatory properties (Kowalczyk et al, 2010). Proanthocyanidins exert antineoplasic effects by inducing cytotoxicity towards some cancer cells (Chatelain et al, 2011), by cell cycle arrest and induction of apoptosis (Kaur et al, 2008).…”

Combination Approach: the Future of the War Against Cancer

“…Moreover, similar combination had successfully maintained the Cell Biochem Biophys normal levels of essential trace element zinc during lung carcinogenesis [7]. Kowalczyk et al evaluated combination of ellagic acid found in green tea extract and resveratrol present in grapes against skin cancer in mice [14].…”