The tumor proteasome as a novel target for gold(III) complexes: Implications for breast cancer therapy

Abstract

Although cisplatin plays a vital role in the treatment of several types of human cancer, its wide use is limited by the development of drug resistance and associated toxic side effects. Gold and gold complexes have been used to treat a wide range of ailments for many centuries. In recent years, the use of gold(III) complexes as an alternative to cisplatin treatment was proposed due to the similarities of gold and platinum. Gold(III) is isoelectronic with platinum(II) and gold(III) complexes have the same square-planar geometries as platinum(II) complexes, such as cisplatin. Although it was originally thought that gold(III) complexes might have the same molecular target as cisplatin, several lines of data indicated that proteins, rather than DNA, are targeted by gold complexes. We have recently evaluated cytotoxic and anti-cancer effects of several gold(III) dithiocarbamates against human breast cancer cells in vitro and in vivo. We have identified the tumor proteasome as an important target for gold(III) complexes and have shown that proteasome inhibition by gold(III) complexes is associated with apoptosis induction in breast cancer cells in vitro and in vivo. Furthermore, treatment of human breast tumor-bearing nude mice with a gold(III) dithiocarbamate complex was associated with tumor growth inhibition, supporting the significance of its potential development for breast cancer treatment.

Stable Anticancer Gold(III)–Porphyrin Complexes: Effects of Porphyrin Structure

“…[4] In recent years, a number of goldA C H T U N G T R E N N U N G (III) complexes were reported to be more effective at inhibiting cancer cells than clinically used cisplatin, with IC 50 values at the micromolar level. [5] However, most of these cytotoxic goldA C H T U N G T R E N N U N G (III) complexes are susceptible to spontaneous reduction to gold(I) and colloidal gold under physiological conditions. [5,6] In the literature, there are only a few cytotoxic goldA C H T U N G T R E N N U N G (III) complexes, including [Au III A C H T U N G T R E N N U N G (bipy c -H)(OH)]A C H T U N G T R E N N U N G [PF 6 ] (bipy c -H = deprotonated 6-(1,1-dimethylbenzyl)-2,2'-bipyridine), [6u] [Au III -A C H T U N G T R E N N U N G (dmamp)Cl 2 ] (dmamp = 2-(dimethylaminomethyl)phenyl), [7] [Au III m A C H T U N G T R E N N U N G (C^N^C) m L] n + (m = 1-3; n = 0-3; HC^N^CH = 2,6-diphenylpyridine), [8] and the [AuA C H T U N G T R E N N U N G (Por)] + complexes (Por = porphyrinato ligand) [9] that are known to exhibit significant anticancer activity, as well as excellent solution stability.…”

Synthesis of novel macrocyclic Schiff's‐base and its complexes having N2O2 group of donor atoms. Characterization and anticancer screening are studied

“…[7,8] Hydrazones are characterized by the presence of azomethine group (─CH═N─); they are good polydentate chelating agents that can form a variety of complexes with various transition metals and inner transition metals. [9][10][11][12][13][14][15][16][17] Metal complexes containing improved organic ligands are widely used in cancer chemotherapy. The great success in the clinical treatment of human malignancies has stimulated research in the area of inorganic antitumor agents, the application of which can be hampered by severe toxicity and development of resistance during therapy.…”

Gold Ion–Angiotensin Peptide Interaction by Mass Spectrometry

“…Since gold(III) ion is isoelectronic with platinum(II) ion and it forms square-planar complexes as in cisplatin, gold(III) compounds are explored for potential anticancer activities. A number of gold(III) complexes with ligands such as bipyridyls, dithiocarbamato, porphyrins, and quinolines, which display in vitro and in vivo potent anticancer activities and reduced systemic toxicity compared with the cisplatin, have been synthesized [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Small peptides such as S-phenylalanine-S-phenylalanine, glycyl-alaline, glycyl-histidine, alanyl-phenylalanine, glycyl-S-serine, glycyl-alanyl-alanine, glycyl-glycyl-histidine, and glycyl-glycyl-methyonyl-glycyl-glycine are another class of ligands of gold(III) ion that have been investigated for development of potential anticancer drugs [18][19][20][21][22][23][24].…”