O6-Methylguanine-DNA Methyltransferase (MGMT): Challenges and New Opportunities in Glioma Chemotherapy

Chemoresistance has been a significant problem affecting the efficacy of drugs targeting tumors for decades. MGMT, known as O-6-methylguanine-DNA methyltransferase, is a DNA repair enzyme that plays an important role in chemoresistance to alkylating agents. Hence, MGMT is considered a promising target for tumor treatment. Several methods are employed to detect MGMT, each with its own advantages and disadvantages. Some of the detection methods are; immunohistochemistry, methylation-specific PCR (MSP), pyrophosphate sequencing, MGMT activity test, and real-time quantitative PCR. Methylation of MGMT promoter is a key predictor of whether alkylating agents can effectively control glioma cells. The prognostic value of MGMT in glioma is currently being explored. The expression of MGMT gene mainly depends on epigenetic modification-methylation of CpG island of MGMT promoter. CpG island covers a length of 762 bp, with 98 CpG sites located at the 5' end of the gene, ranging from 480 to 1,480 nucleotides. The methylation sites and frequencies of CpG islands vary in MGMT-deficient tumor cell lines, xenografts of glioblastoma and in situ glioblastoma. Methylation in some regions of promoter CpG islands is particularly associated with gene expression. The change in the methylation status of the MGMT promoter after chemotherapy, radiotherapy or both is not completely understood, and results from previous studies have been controversial. Several studies have revealed that chemotherapy may enhance MGMT expression in gliomas. This could be through gene induction or selection of high MGMT-expressing cells during chemotherapy. Selective survival of glioma cells with high MGMT expression during alkylating agent therapy may change MGMT status in case of recurrence. Several strategies have been pursued to improve the anti-tumor effects of temozolomide. These include the synthesis of analogs of O-6-meG such as O-6-benzylguanine (O-6-BG) and O-6-(4-bromothenyl) guanine (O-6-BTG), RNAi, and viral proteins. This review describes the regulation of MGMT expression and its role in chemotherapy, especially in glioma. Targeting MGMT seems to be a promising approach to overcome chemoresistance. Further studies exploring new agents targeting MGMT with better curative effect and less toxicity are advocated. We anticipate that these developments will improve the current poor prognosis of glioma patients.