Epigallocatechin Gallate Preferentially Inhibits O6-Methylguanine DNA-Methyltransferase Expression in Glioblastoma Cells Rather than in Nontumor Glial Cells.

ABSTRACT

OBJECTIVE: O6-methylguanine (O6-meG) DNA-methyltransferase (MGMT) is a main regulator of temozolomide (TMZ) resistance in glioblastomas. Some MGMT inhibitors have been studied in clinical trials but with very little success, because their inhibiting effects were not tumor-selective, and often cause severe toxicity in normal tissues in the presence of TMZ. The goal of this study is to explore whether Epigallocatechin gallate (EGCG), a natural small molecule, could preferentially modulate MGMT in glioblastoma cells. METHODS: Two MGMT-positive glioblastoma cell lines (GBM-XD and T98G) and one nontumor glial cell culture (GliaX) were included in this study. The MGMT promoter methylation status, mRNA abundance, and protein levels were determined before and after EGCG treatment. The mechanisms were characterized. RESULTS: EGCG substantially suppressed mRNA and protein expression of MGMT, and reversed TMZ resistance in MGMT-positive GBM-XD and T98G cells via the WNT/ß-catenin pathway. EGCG prevented ß-catenin translocation into the nucleus and might directly inhibit the transcription factors TCF1 and LEF1. Meanwhile, EGCG enhanced the MGMT expression in the nontumor glial cells, through inhibition of the DNMT1 and demethylation of MGMT promoter. CONCLUSIONS: EGCG preferentially inhibits MGMT and enhances TMZ cytotoxicity in glioblastoma cells rather than in nontumor glial cells.