Alkyl gallates, derived from structural studies of green tea catechins, as new candidates for cancer preventive agents

A116

Green tea is now an acknowledged cancer preventive beverage, and its active constituents are green tea catechins, such as (-)-epigallocatechin gallate (EGCG). The study of the strucure-function relationship of green tea catechins has revealed that the galloyl group of EGCG is essential for cancer preventive activity. To develop new cancer preventive drugs, we thus focused on alkyl gallates with various lengths of fatty acid chains. Eleven alkyl gallates were kindly provided by Dr. Tomihiko Higuchi, The University of Tokushima. We found that inhibitory activities of cancer cell growth with the alkyl gallates increased associated with length of fatty acid chains: Specifically, octyl gallate (C=8), nonyl gallates (C=9), and lauryl gallate (C=12) showed the strongest inhibitory activities among the 11 compounds. These alkyl gallates also inhibited growth of Bhas 42 cells (BALB/3T3 cells transfected with v-H-ras gene, a standard model of initiated cells) 100-fold stronger than EGCG did: IC50 values were 0.6 μM for lauryl gallate, 0.8 μM for octyl gallate, 130 μM for EGCG and 140 μM for gallic acid. Furthermore, lauryl and octyl gallates inhibited in vitro transformation of Bhas 42 cells induced by okadaic acid, a tumor promoter, suggesting that they are anti-tumor promoters. We have previously shown that strong expressions of growth-arrest and DNA damage-inducible gene (GADD153) and p21WAF1 are essential mechanisms for synergistic induction of cancer preventive activity with EGCG and cancer preventive agents such as COX-2 inhibitors and retinoids. Interestingly, treatment with octyl, nonyl and lauryl gallates alone strongly induced GADD153 gene expression in human lung cancer cell line PC-9 without any use of cancer preventive agents. Moreover, the analysis of cell cycles of PC-9 cells treated with lauryl gallate by flow cytometry revealed inhibition of G1/S transition. All these results strongly suggest that alkyl gallates with long fatty acid chains are new candidates for cancer preventive agents.