Gold(III)-dithiocarbamato complexes induce cancer cell death triggered by thioredoxin redox system inhibition and activation of ERK pathway.
Although gold compounds are now recognized as promising anticancer agents, so far only gold(I) derivatives have been investigated for this purpose, whereas the use of gold(III) complexes has been hampered by their poor stability under physiological conditions. We have therefore carried out studies on selected gold(III) anticancer agents, showing enhanced stability due to the presence of chelating dithiocarbamato ligands. We found that they induce cancer cell death through both apoptotic and nonapoptotic mechanisms. They also inhibit thioredoxin reductase activity, generate free radicals, modify some mitochondrial functions, and increase ERK1/2 phosphorylation. Based on our results, we propose and discuss a working model suggesting that deregulation of the thioredoxin reductase/thioredoxin redox system is a major mechanism involved in the anticancer activity of the investigated gold(III)-dithiocarbamato complexes.
Saggioro
Daniela
D
Molecular Immunology and Diagnostic Oncology, Istituto Oncologico Veneto IRCCS, Via Gattamelata 64, Padova 35128, Italy.
Rigobello
Maria Pia
MP
Paloschi
Lucia
L
Folda
Alessandra
A
Moggach
Stephen A
SA
Parsons
Simon
S
Ronconi
Luca
L
Fregona
Dolores
D
Bindoli
Alberto
A
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008928:Mitochondria / Q000378:metabolism; D050607:Organogold Compounds / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D051381:Rats; D013859:Thiocarbamates / Q000737:chemistry / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*; D013879:Thioredoxins / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005609:Free Radicals; D008024:Ligands; D050607:Organogold Compounds; D013859:Thiocarbamates; D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase; D048049:Extracellular Signal-Regulated MAP Kinases