Posttranslational Regulation of O6-Methylguanine-DNA Methyltransferase (MGMT) and New Opportunities for Treatment of Brain Cancers

Title:Posttranslational Regulation of O6-Methylguanine-DNA Methyltransferase (MGMT) and New Opportunities for Treatment of Brain Cancers

Volume: 16 Issue: 6

Author(s): Kalkunte S. Srivenugopal, Amit Rawat, Suryakant K. Niture, Ameya Paranjpe, Chinavenmani Velu, Sanjay N. Venugopal, Hanumantha Rao Madala, Debasish Basak and Surendra R. Punganuru

Affiliation:

Keywords: Alkylating agents, DNA repair, Drug repurposing, gliomas, Protein glutathionylation, Reactive cysteines.

Abstract: O⁶-Methylguanine-DNA-methyltransferase (MGMT) is an antimutagenic DNA repair protein highly expressed in human brain tumors. Because MGMT repairs the mutagenic, carcinogenic and cytotoxic O⁶-alkylguanine adducts, including those generated by the clinically used anticancer alkylating agents, it has emerged as a central and rational target for overcoming tumor resistance to alkylating agents. Although the pseudosubstrates for MGMT [O⁶-benzylguanine, O⁶-(4- bromothenyl)guanine] have gained attention as powerful and clinically-relevant inhibitors, bone marrow suppression due to excessive alkylation damage has diminished this strategy. Our laboratory has been working on various posttranslational modifications of MGMT that affect its protein stability, DNA repair activity and response to oxidative stress. While these modifications greatly impact the physiological regulation of MGMT, they also highlight the opportunities for inactivating DNA repair and new drug discovery in this specific area. This review briefly describes the newer aspects of MGMT posttranslational regulation by ubiquitination, sumoylation and glutathionylation and reveals how the reactivity of the active site Cys145 can be exploited for potent inhibition and depletion of MGMT by thiol-reacting drugs such as the disulfiram and various dithiocarbamate derivatives. The possible repurposing of these nontoxic and safe drugs for improved therapy of pediatric and adult brain tumors is discussed.

Cite this article as:

Srivenugopal S. Kalkunte, Rawat Amit, Niture K. Suryakant, Paranjpe Ameya, Velu Chinavenmani, Venugopal N. Sanjay, Madala Rao Hanumantha, Basak Debasish and Punganuru R. Surendra, Posttranslational Regulation of O6-Methylguanine-DNA Methyltransferase (MGMT) and New Opportunities for Treatment of Brain Cancers, Mini-Reviews in Medicinal Chemistry 2016; 16 (6) . https://dx.doi.org/10.2174/1389557515666150722101046