title: Posttranslational Regulation of O(6)-Methylguanine-DNA Methyltransferase (MGMT) and New Opportunities for Treatment of Brain Cancers.
abstract: O(6)-Methylguanine-DNA-methyltransferase (MGMT) is an antimutagenic DNA repair protein highly expressed in human brain tumors. Because MGMT repairs the mutagenic, carcinogenic and cytotoxic O(6)-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 [O(6)-benzylguanine, O(6)-(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.
authors.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. Kalkunte.Srivenugopal@ttuhsc.edu.
authors.forename: Kalkunte S
authors.initials: KS
authors.lastname: Srivenugopal
authors.forename: Amit
authors.initials: A
authors.lastname: Rawat
authors.forename: Suryakant K
authors.initials: SK
authors.lastname: Niture
authors.forename: Ameya
authors.initials: A
authors.lastname: Paranjpe
authors.forename: Chinavenmani
authors.initials: C
authors.lastname: Velu
authors.forename: Sanjay N
authors.initials: SN
authors.lastname: Venugopal
authors.forename: Hanumantha Rao
authors.initials: HR
authors.lastname: Madala
authors.forename: Debasish
authors.initials: D
authors.lastname: Basak
authors.forename: Surendra R
authors.initials: SR
authors.lastname: Punganuru
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003545:Cysteine / Q000032:analysis / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy / Q000379:methods; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000032:analysis / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011499:Protein Processing, Post-Translational
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019853:O(6)-Methylguanine-DNA Methyltransferase; D005978:Glutathione; D003545:Cysteine