Inhibition of the Proteasome Activity by Gallium(III) Complexes Contributes to Their Anti–Prostate Tumor Effects

Abstract

The investigation of metal-based complexes with potential antitumor activity has been of paramount importance in recent years due to the successful use of cisplatin against various cancers. Gallium(III) and subsequently developed gallium(III)-containing complexes have shown promising antineoplastic effects when tested in a host of malignancies, specifically in lymphomas and bladder cancer. However, the molecular mechanism responsible for their anticancer effect is yet to be fully understood. We report here for the first time that the proteasome is a molecular target for gallium complexes in a variety of prostate cancer cell lines and in human prostate cancer xenografts. We tested five gallium complexes (1-5) in which the gallium ion is bound to an NN ¶O asymmetrical ligand containing pyridine and substituted phenolate moieties in a 1:2 (M/L) ratio. We found that complex 5 showed superior proteasome inhibitory activity against both 26S proteasome (IC 50 , 17 Mmol/L) and purified 20S (IC 50 , 16 Mmol/L) proteasome. Consistently, this effect was associated with apoptosis induction in prostate cancer cells. Additionally, complex 5 was able to exert the same effect in vivo by inhibiting growth of PC-3 xenografts in mice (66%), which was associated with proteasome inhibition and apoptosis induction. Our results strongly suggest that gallium complexes, acting as potent proteasome inhibitors, have a great potential to be developed into novel anticancer drugs.

Antimicrobial effect of gallium nitrate against bacteria encountered in burn wound infections

“…Currently, the efficacy and safety of a variety of compounds containing gallium that are widely used to treat cancer and hypercalcemia, have been conrmed. [16][17][18][19][20] The rst investigation of the antimicrobial action of gallium was published in 1931. 21 It has been reported that gallium (Ga 3+ ) exerts a signicant inhibitory activity against numerous bacteria including Staphylococcus aureus, methicillin-resistant S. aureus, Rhodococcus equi, Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli.…”

Metallomics related to gallium compounds: biochemical and xenobiochemical aspects

“…A series of [Ga(LX) 2 ]ClO 4 compounds ((LX) -= deprotonated form of ligands containing pyridine and 4,6-substituted phenol moieties with X = methoxy, nitro, chloro, bromo, and iodo) displayed growth-inhibition activity on cisplatin-resistant human neuroblastoma cells [48,49]. This class of compounds was also shown to target the proteasome [50].…”

Metal-Based Compounds as Proteasome-Inhibitory Anti Cancer Drugs

“…A series of gallium complexes with two pyridine phenolate ligands with asymmetric NN'O donor groups were tested for their ability to inhibit proteasome activity and induce apoptosis in C4-2B prostate cancer cells. Chloro-, bromo-and iodo-substituted species [37] were able to inhibit purified proteasome (IC 50 =46, 27 and 16 µM, respectively) and cellular proteasome (IC 50 =48, 28 and 17 µM, respectively) activities [38]. Ubiquitinated protein and p27 accumulation, AR suppression and apoptosis induction, all associated with proteasome inhibition, were observed following treatment with these complexes.…”

“…Ubiquitinated protein and p27 accumulation, AR suppression and apoptosis induction, all associated with proteasome inhibition, were observed following treatment with these complexes. Mice-bearing prostate cancer xenografts treated with the bromo-substituted complex exhibited inhibition of tumour growth, associated with the appearance of apoptotic indices [38]. Thus, gallium may serve as a viable option for the specific treatment of tumour cells.…”