title: Molecular mechanisms and proposed targets for selected anticancer gold compounds.
abstract: Nowadays, gold compounds constitute a family of very promising experimental agents for cancer treatment. Indeed, several gold(I) and gold(III) compounds were shown to manifest outstanding antiproliferative properties in vitro against selected human tumor cell lines and some of them performed remarkably well even in tumor models in vivo. Notably, the peculiar chemical properties of the gold centre impart innovative pharmacological profiles to gold-based metallodrugs most likely in relation to novel molecular mechanisms. The precise mechanisms through which cytotoxic gold compounds produce their biological effects are still largely unknown. Within this frame, the major aim of this review is to define the possible modes of action and the most probable biomolecular targets for a few representative gold compounds on which extensive biochemical and cellular data have been gathered. In particular, we will focus on auranofin and analogues, on gold(III) porphyrins and gold(III) dithiocarbamates. For these three families markedly distinct molecular mechanisms were recently invoked: a direct mitochondrial mechanism involving thioredoxin reductase inhibition in the case of the gold(I) complexes, the influence on some apoptotic proteins--i.e. MAPKs and Bcl-2--for gold(III) porphyrins, and the proteasome inhibition for gold(III) dithiocarbamates. In a few cases the distinct mechanisms may overlap. The general perspectives for the development of new gold compounds as effective anticancer agents with innovative modes of action are critically discussed.
authors: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. angela.casini@epfl.ch
authors: Angela
authors: A
authors: Casini
authors: Luigi
authors: L
authors: Messori
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D006046:Gold / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050607:Organogold Compounds / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D011166:Porphyrins / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013859:Thiocarbamates / Q000737:chemistry / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050607:Organogold Compounds; D011166:Porphyrins; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D013859:Thiocarbamates; D006046:Gold; D013880:Thioredoxin-Disulfide Reductase; D046988:Proteasome Endopeptidase Complex