Tumor migration/invasion is the main cause of tumor progression and STAT3 is needed to enhance tumor migration/invasion by up-regulating MMP-9. Thus, agents that inhibit STAT3 activation may be used as an anticancer drug. We present herein that 6-methyl-2-propylimino-6, 7-dihydro-5H-benzo [1, 3]-oxathiol- 4-one (LYR71) , a derivative of trimeric resveratrol, has an anticancer activity through inhibition of STAT3 activation. We found that LYR71 suppressed STAT3 activation and inhibited the expression and activity of MMP-9 in RANTES-stimulated breast cancer cells. In addition, LYR71 reduced RANTES-induced MMP-9 transcripts by blocking STAT3 recruitment, dissociating p300 and deacetylating histone H3 and H4 on the MMP-9 promoter. Furthermore, LYR71 inhibited tumor migration/invasion in RANTES-treated breast cancer cells and consequently blocked tumor progression in tumor-bearing mice. Taken together, the results of this study suggest that LYR71 can be therapeutically useful due to the inhibition effect of STAT3-mediated MMP-9 expression in breast cancer cells.
Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Bicyclo Compounds, Heterocyclic/chemistry/*pharmacology ; Blotting, Western ; Breast Neoplasms/genetics/metabolism/pathology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Chromatin Immunoprecipitation ; Female ; Gene Expression/drug effects ; Humans ; Imines/chemistry/*pharmacology ; Immunohistochemistry ; Mammary Neoplasms, Experimental/pathology/prevention & control ; Matrix Metalloproteinase 9/genetics/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Structure ; Phosphorylation/drug effects ; Reverse Transcriptase Polymerase Chain Reaction ; STAT3 Transcription Factor/genetics/*metabolism ; Stilbenes/chemistry ; Xenograft Model Antitumor Assays/methods