title: Diethyldithiocarbamate complex with copper: the mechanism of action in cancer cells.
abstract: The idea of "repurposing" of existing drugs provides an effective way to develop and identify new therapies. Disulfiram (Antabuse), a drug commonly used for the treatment of alcoholism, shows promising anticancer activity in both preclinical and clinical studies. In the human body, disulfiram is rapidly converted to its reduced metabolite, diethyldithiocarbamate. If copper ions are available, a bis(diethyldithiocarbamate)-copper(II) complex is formed. Disulfiram's selective anticancer activity is attributed to the copper(II) complex's ability to inhibit the cellular proteasome. It is assumed that the complex inhibits the proteasome by a mechanism that is distinct to the clinically used drug bortezomib, targeting the 19S rather than the 20S proteasome. This difference could be explained by inhibition of the JAMM domain of the POH1 subunit within the lid of the 19S proteasome.
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 11, 78371 Olomouc, Czech Republic. zdenek.skrott@centrum.cz
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Skrott
authors.forename: Boris
authors.initials: B
authors.lastname: Cvek
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D003300:Copper / Q000737:chemistry*; D004050:Ditiocarb / Q000737:chemistry*; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D056831:Coordination Complexes; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003300:Copper; D004050:Ditiocarb; D046988:Proteasome Endopeptidase Complex