Novel Pathways of Oxidative and Nitrosative Inactivation of the Human MGMT Protein in Colon Cancer and Glioblastoma Cells: Increased Efficacy of Alkylating Agents In Vitro and In Vivo
Debasish Basak, Agm Mostofa, Hanumantha Rao Madala, Kalkunte S. Srivenugopal
TL;DR
This study shows that inactivating the MGMT protein through oxidative and nitrosative methods increases the effectiveness of alkylating agents in treating colon cancer and glioblastoma.
Contribution
The study introduces novel redox-driven strategies to inactivate MGMT, enhancing the efficacy of alkylating agents in cancer therapy.
Findings
hGTX and spermine NONOate inhibited MGMT activity in various tumor cells.
Combining these agents with alkylating drugs increased DNA damage and tumor growth delay in xenograft models.
N6022 extended nitrosylated MGMT retention, prolonging DNA repair deficiency.
Abstract
Background: O6-Methylguanine-DNA methyltransferase (MGMT) is a unique antimutagenic DNA repair protein that plays a crucial role in conferring resistance to various alkylating agents in brain tumor therapy. In this study, we exploited the susceptibility of the active site Cys145 of MGMT for thiolation and nitrosylation, both of which inactivate the enzyme. Methods: We designed a redox perturbing glutathione mimetic, a platinated homoglutathione disulfide (hGTX) by adding small amounts of cisplatin (1000:10) and used a nitric oxide-donor spermine NONOate. N6022, a potent inhibitor of S-nitrosoglutathione reductase was used to extend the retention of nitrosylated MGMT in tumor cell culture and subcutaneous xenografts. Results: Both hGTX and spermine NONOate inhibited MGMT activity in HT29, SF188, T98G, and other brain tumor cells. There was a robust increase in the alkylation-induced DNA…
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Taxonomy
TopicsEpigenetics and DNA Methylation · Cancer Research and Treatments · Amino Acid Enzymes and Metabolism