Chemistry, antiproliferative properties, tumor selectivity, and molecular mechanisms of novel gold(III) compounds for cancer treatment: a systematic study.
The antiproliferative properties of a group of 13 structurally diverse gold(III) compounds, including six mononuclear gold(III) complexes, five dinuclear oxo-bridged gold(III) complexes, and two organogold(III) compounds, toward several human tumor cell lines were evaluated in vitro using a systematic screening strategy. Initially all compounds were tested against a panel of 12 human tumor cell lines, and the best performers were tested against a larger 36-cell-line panel. Very pronounced antiproliferative properties were highlighted in most cases, with cytotoxic potencies commonly falling in the low micromolar--and even nanomolar--range. Overall, good-to-excellent tumor selectivity was established for at least seven compounds, making them particularly attractive for further pharmacological evaluation. Compare analysis suggested that the observed antiproliferative effects are caused by a variety of molecular mechanisms, in most cases "DNA-independent," and completely different from those of platinum drugs. Remarkably, some new biomolecular systems such as histone deacetylase, protein kinase C/staurosporine, mammalian target of rapamycin/rapamycin, and cyclin-dependent kinases were proposed for the first time as likely biochemical targets for the gold(III) species investigated. The results conclusively qualify gold(III) compounds as a promising class of cytotoxic agents, of outstanding interest for cancer treatment, while providing initial insight into their modes of action.
Casini
Angela
A
Laboratory of Organometallic and Medicinal Chemistry, Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. angela.casini@epfl.ch
Kelter
Gerhard
G
Gabbiani
Chiara
C
Cinellu
Maria Agostina
MA
Minghetti
Giovanni
G
Fregona
Dolores
D
Fiebig
Heinz-Herbert
HH
Messori
Luigi
L
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D055664:Electrochemical Techniques; D017612:Gold Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D011419:Propidium; D013053:Spectrophotometry; D018709:Statistics, Nonparametric; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D017612:Gold Compounds; D007202:Indicators and Reagents; D011419:Propidium