Abstract
Temozolomide (TMZ) is an alkylating agent currently used as first-line therapy for gliomas treatment due to its DNA-damaging effect. However, drug resistance occurs, preventing multi-cycle use of this chemotherapeutic agent. One of the major mechanisms of cancer drug resistance is enhanced activity of a DNA repair enzyme, O6-methylguanine-DNA-methyltransferase (MGMT), which counteracts chemotherapy-induced DNA alkylation and is a key component of chemoresistance. MGMT repairs TMZ-induced DNA lesions, O6-meG, by transferring the alkyl group from guanine to a cysteine residue. This review provides an overview of recent advances in the field, with particular emphasis on the inhibitors of MGMT and underlying mechanisms. Literature search was performed through PubMed and all relevant articles were reviewed, with particular attention to MGMT, its role in TMZ-resistant gliomas, effects of MGMT inhibitors and the underlying mechanisms. Several strategies are currently being pursued to improve the therapeutic efficacy of TMZ via inhibition of MGMT to reduce chemoresistance and improve overall survival. MGMT may be a promising target for the treatment of TMZ-resistant gliomas.
Highlights
Resistance to TMZ emerges with prolonged treatment, mainly due to O6-methylguanine-DNA-methyltransferase (MGMT), which repairs O6-methylguanine (O6-meG) lesion by transferring the alkyl group from guanine to a cysteine residue, which posts a major therapeutic challenge
DNA replication forks, which is mediated by the ATRinteracting protein (ATRIP), a prerequisite for ATR.[18]
The formation of this nucleoprotein filament at single-stranded DNA (ssDNA) is promoted and stabilized by BRCA2.25,26 Both Rad[51] and BRCA2 are essential for homologous recombination (HR) in mammalian cells, the functions of Rad[51] and BRCA2 in other repair pathways have not been elucidated
Summary
How to overcome dose-limiting myelosuppressive toxicity of TMZ while maintaining its efficacy?. O6-meG is processed into DNA double-strand breaks (DSBs) in a DNA MMR-dependent manner, requiring two rounds of DNA replication (Figure 2).[15,16] These DSBs may trigger apoptotic cell death in glioblastoma multiforme (GBM).[7] O6-meG is the best example of how a defined DNA lesion triggers the DNA damage response This small DNA adduct does not block DNA replication, it occurs in MGMT lacking cancer cells and may be responsible for the majority of mutations, recombination, clastogenicity, and apoptotic effects of methylating agents that have the ability to methylate oxygen in DNA.[17] One of the key transducing kinases of the
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