CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Novel anticancer metallodrugs

A broad interest in the area of metal-based anticancer drugs was developed after the serendipitous discovery of the anticancer properties of cisplatin and other platinum(II) complexes. Several metal compounds (ruthenium, palladium, titanium, gold, tin etc.) were taken under consideration for their antitumor effects. In particular gold complexes, already in the clinics for the treatment of rheumatoid arthritis, were soon considered as anticancer agents. Presently, the thioredoxin system, formed by NADPH, thioredoxin (Trx) and thioredoxin reductase (TrxR) is considered a major cellular target of an increasing number of anticancer drugs. Thioredoxin reductase, present both in mitochondria and the cytosol, is characterized by the presence of a selenol group at its active site that easily reacts with "soft" metals ions.

Results and Perspectives

We tested a very large array of gold(I) or gold(III) complexes, either commercially available or newly synthesized, which potently inhibit both cytosolic and mitochondrial thioredoxin reductases at extremely low concentrations (IC50 value are in the low nanomolar range). In intact mitochondria gold(I/III) complexes induce swelling, decrease of membrane potential, release of cytochrome c, decrease of total thiols, increase in thioredoxin oxidation and production of hydrogen peroxide. Various types of tumor cells treated with gold complexes show loss of viability. Cell death occurs mainly by apoptosis as observed by nuclear fragmentation. Furthermore, gold complexes were shown to stimulate ROS formation in ovarian cancer cells and HeLa cells estimated as fluorescence enhancement of specific probes. Several signalling pathways of the MAP kinases system were activated by gold complexes such as ERK1/2, JNK and p38. Interestingly, in human ovarian cancer cells resistant to cisplatin, gold(I) complexes (e.g. auranofin), but not cisplatin, are able to stimulate the release of cytochrome c from mitochondria to the cytosol. Consequently, auranofin is able to overcome the resistance to cisplatin and creates the conditions for apoptosis in cisplatin resistant tumor cells. From the reported results a mechanism of cell death by gold(I/III) compounds has been devised (see Figure).

 

The mitochondrial respiratory chain produces hydrogen peroxide that oxidizes thioredoxin by means of peroxiredoxin. Mitochondrial thioredoxin reductase (TrxR2), inhibited by gold(I/III) complexes, is unable to reduce back the oxidized thioredoxin that, in turn, prevents the removal of hydrogen peroxide. Both oxidized thioredoxin and hydrogen peroxide act on mitochondrial targets leading to the opening of the permeability transition pore and/or to an increase of the permeability of the outer membrane. Hydrogen peroxide leaks out of the mitochondrial membrane into the cytosol where cytosolic thioredoxin cannot be maintained reduced by the gold(I/III)-inhibited cytosolic thioredoxin reductase (TrxR1). In the cytosol, oxidized thioredoxin stimulates the MAP kinases pathway. Other metal complexes were also tested such as ruthenium complexes that appear to exert their inhibitory effect essentially on the mitochondrial isoform of thioredoxin reductase.

In summary:

  • Mitochondria and thioredoxin reductase are specific targets of gold complexes at variance with cisplatin that acts essentially on DNA.
  • Gold complexes, widely used in the treatment of rheumatoid arthritis, can be potentially developed as anticancer agents.
  • Synergistic administration of gold compounds may enhance the antitumor profile of established anticancer drugs.
  • An improved understanding of the molecular and biochemical mechanisms of gold complexes will provide the impetus for new advances in the medical use of gold drugs.

Publications

  • Gandin V, Fernandes AP, Rigobello MP, Dani B, Sorrentino F, Tisato F, Bj√∂rnstedt M, Bindoli A, Sturaro A, Rella R, Marzano C (2010) Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase. Biochem. Pharmacol. 79:90-101.
  • Casini A, Gabbiani C, Sorrentino F, Rigobello MP, Bindoli A, Geldbach TJ, Marrone A, Re N, Hartinger CG, Dyson PJ, Messori L (2008) Emerging protein targets for anticancer metallodrugs: inhibition of thioredoxin reductase and cathepsin B by antitumor ruthenium(II)-arene compounds. J. Med. Chem. 51:6773-81.
  • Rigobello MP, Folda A, Dani B, Menab√≤ R, Scutari G, Bindoli A (2008) Gold(I) complexes determine apoptosis with limited oxidative stress in Jurkat T cells. Eur. J. Pharmacol. 582:26-34.
  • Mura P, Camalli M, Bindoli A, Sorrentino F, Casini A, Gabbiani C, Corsini M, Zanello P, Rigobello MP, Messori L (2007) Activity of rat cytosolic thioredoxin reductase is strongly decreased by trans-[bis(2-amino-5- methylthiazole)tetrachlororuthenate(III)]: first report of relevant thioredoxin reductase inhibition for a ruthenium compound. J. Med. Chem. 50:5871-4.
  • Saggioro D, Rigobello MP, Paloschi L, Folda A, Moggach SA, Parsons S, Ronconi L, Fregona D, Bindoli A (2007) Gold(III)-dithiocarbamato complexes induce cancer cell death triggered by thioredoxin redox system inhibition and activation of ERK pathway. Chem. Biol. 14:1128-39.
  • Marzano C, Gandin V, Folda A, Scutari G, Bindoli A, Rigobello MP (2007) Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells. Free Radic. Biol. Med. 42:872-81.

Collaborations

  • Angela Casini, Paul Dyson, Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale Lausanne, Lausanne, Switzerland.
  • Luigi Messori, Chiara Gabbiani, Dipartimento di Chimica, Università di Firenze, Sesto Fiorentino, Firenze, Italy.
  • Dolores Fregona, Luca Ronconi, Dipartimento di Scienze Chimiche, Università di Padova, Padova, Italy.
  • Anna Rita Bilia, Anastasia Karioti, Dipartimento di Scienze Farmaceutiche, Università di Firenze, Sesto Fiorentino, Firenze, Italy.

 

PI photo

Alberto Bindoli

Contact information

email  E-mail

email  049 8276138

Participating staff

Maria Pia Rigobello
Assistant professor

Guido Scutari
Associate professor

Alessandra Folda
Laureate technician