Strategies to Improve the Killing of Tumors Using Temozolomide: Targeting the DNA Repair Protein MGMT

Abstract

Alkylating agents such as temozolomide (TMZ) are effective anticancer drugs for treating a variety of solid tumors including melanoma, glioma, and astrocytoma. TMZ exerts its effects mainly via the mutagenic product O(6)-methylguanine, a cytotoxic DNA lesion. This damage may be repaired by the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT), a key player in the resistance of cancers to TMZ. Several strategies are presently being pursued to improve the killing of tumor cells by TMZ, with inhibition of MGMT being the most promising. In this review, we provide an overview of recent advances in this field.

Pine (Pinus morrisonicola Hayata) Needle Extracts Sensitize GBM8901 Human Glioblastoma Cells to Temozolomide by Downregulating Autophagy and O6-Methylguanine-DNA Methyltransferase Expression

“…MGMT expression in glioblastoma cells is the most critical determinant of TMZ resistance. 20 MGMT counteracts the effects of TMZ by removing DNA methyl adducts, suggesting that downregulation of MGMT is effective for the management of TMZ-resistant glioblastoma. 21 To date, many clinical trials have aimed to modulate MGMT expression for increasing TMZ efficiency.…”

Temozolomide induces autophagy via ATM-AMPK-ULK1 pathways in glioma

“…The primary cytotoxic lesion, the O 6 MeG DNA adduct, may be eliminated by O 6 -methylguanine DNA methyltransferase (MGMT) in gliomas expressing this DNA repair enzyme (4,8). Since the MGMT promoter in almost half of the glioblastoma specimens was methylated and the MGMT promoter methylation status of the primary tumor was retained at recurrence, other chemoresistance mechanisms are critical for TMZ tolerance in MGMT-negative glioblastoma (9,10).…”

The effect of ascorbic acid over the etoposide and temozolomide mediated cytotoxicity in glioblastoma cell culture: a molecular study

“…The therapeutic benefit of temozolomide depends on its ability to alkylate/ methylate DNA, which most often occurs at the N (nitrogen) 7 and O (oxygen) 6 positions of guanine residues, causing a base pair mismatch. This methylation damages the DNA, and when mismatch repair (MMR) enzymes attempt to remove the 8-oxo-dGuo adduct, they produce single and double-strand breaks in the DNA and trigger cell death (11,13). Removing the methyl guanine adducts causes a decrease in the guanine residue concentrations.…”