Abstract #4429: 1,2,3,4,6-Penta-O-galloyl-beta-D-glucose suppresses proliferation and induces apoptosis in human breast cancer cells via Stat3 inhibition

The activation of STAT3 plays a critical role in the proliferation and survival of various cancer cells including breast cancer. Thus, STAT3 can be a potential target for the chemoprevention and treatment of breast cancer. Here, we tested 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) isolated from the gallnut of Rhus chinensis MILL, for its ability to suppress STAT3 phosphorylative activation (Tyr705). We have found that PGG, a polyphenolic compound, inhibited the constitutive and IL-6-inducible STAT3 phosphorylation (Tyr705) in the aggressive estrogen-independent MDA-MB-231 triple negative (ER-, PR- and HER2-) breast cancer cells and MCF-7 estrogen-dependent breast cancer cells, respectively, in a dose (5, 10 microM)- and time-dependent manner. The STAT3 suppression was associated with the inhibition of its upstream kinases such as JAK1, c-Src and the de-phosphorylation of Akt, and ERK1/2. The protein phosphatase inhibitor vanadate dose-dependently reversed the PGG-induced down-regulation of STAT3 phosphorylation, implying an involvement of a protein tyrosine phosphatase to de-phosphorylate pSTAT3. Consistently, PGG upregulated the expression of the tyrosine phosphatase SHP-1 at mRNA and protein levels. In addition, PGG downregulated the expression of STAT3 target genes such as cyclin D1, Bcl-2, and VEGF and significantly potentiated the cytocidal effects of the therapeutic drugs paclitaxel and doxorubicin in MDA-MB-231 cells. Interestingly, immortalized non-transformed breast epithelial cells MCF-10A were much less sensitive than the cancer cells to PGG for growth suppression, supporting a certain extent of selectivity against breast neoplastic cells. Overall, these findings suggest that PGG may be a potential cancer chemopreventive or treatment agent for breast cancer, in part through inhibiting the STAT3 signaling pathway. Studies are ongoing for the in vivo validation of the anti-breast cancer efficacy and STAT3 as a target of PGG. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4429.