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:Department of Biomedical Sciences and Center for Cancer Biology, School of Pharmacy, Texas Tech University Health Sciences Center, 1406 S. Coulter Drive, Amarillo, TX 79106, USA.
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.
