Pyrrolidine dithiocarbamate-zinc(II) and -copper(II) complexes induce apoptosis in tumor cells by inhibiting the proteasomal activity

Abstract

Zinc and copper are trace elements essential for proper folding, stabilization and catalytic activity of many metalloenzymes in living organisms. However, disturbed zinc and copper homeostasis is reported in many types of cancer. We have previously demonstrated that copper complexes induced proteasome inhibition and apoptosis in cultured human cancer cells. In the current study we hypothesized that zinc complexes could also inhibit the proteasomal chymotrypsin-like activity responsible for subsequent apoptosis induction. We first showed that zinc(II) chloride was able to inhibit the chymotrypsin-like activity of a purified 20S proteasome with an IC 50 value of 13.8 μM, which was less potent than copper(II) chloride (IC 50 5.3 μM). We then compared the potencies of a pyrrolidine dithiocarbamate (PyDT)-zinc(II) complex and a PyDT-copper(II) complex to inhibit cellular proteasomal activity, suppress proliferation and induce apoptosis in various human breast and prostate cancer cell lines. Consistently, zinc complex was less potent than copper complex in inhibiting the proteasome and inducing apoptosis. Additionally, zinc and copper complexes appear to use somewhat different mechanisms to kill tumor cells. Zinc complexes were able to activate calpain-, but not caspase-3-dependent pathway, while copper complexes were able to induce activation of both proteases. Furthermore, the potencies of these PyDT-metal complexes depend on the nature of metals and also on the ratio of PyDT to the metal ion within the complex, which probably affects their stability and availability for interacting with and inhibiting the proteasome in tumor cells.

Synthesis and antimicrobial activities of gold(I) sulfanylcarboxylates

“…Studies on gold complexes have mainly focused on antiarthritic properties [16][17][18][19][20][21], but growing interest is evident in antitumoral [22][23][24], antiparasitic [25] and antibacterial activities. In this last field, the compounds under investigation include a major collection of the type R 3 PAuL, in which the gold atom is coordinated to a phosphine ligand and L is an O- [26,27], N- [28,29], Cl- [30] or S- [29,[31][32][33][34][35] 2 ], Na 3 [Au(mna) 2 ] (H 2 mna 02-mercaptonicotinic acid) [13] and the cationic complexes [Au(L) 2 ](NO 3 ) 3 (L01-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) [34].…”

The proteasomes of two marine decapod crustaceans, European lobster (Homarus gammarus) and Edible crab (Cancer pagurus), are differently impaired by heavy metals

“…Both essential metals, Cu and Zn, showed different and species-specific inhibitory effects on the crustacean proteasomes. Copper is one of the most effective metal proteasome inhibitors known for vertebrate species (Kim et al, 2004;Milacic et al, 2008;Pena et al, 2008). This metal attacks the 20S core complex at the chymotrypsin-like catalytic site (ß5) and affects both the 20S and the 26S proteasome populations (Daniel et al, 2004).…”

New applications of old metal-binding drugs in the treatment of human cancer

“…We found that both the Zn (PyDTC) 2 and Cu (PyDTC) 2 complexes exhibited proteasome inhibitory activity against purified 20S proteasome as well as intact 26S proteasome in MDA-MB-231 cells (128). Accumulation of ubiquitinated proteins and proteasomal target proteins IkB-alpha and p27, associated with proteasome inhibition, and apoptosis associated morphological changes and PARP cleavage occurred in cells treated with either Zn (PyDTC) 2 or Cu (PyDTC) 2 .…”

“…Accumulation of ubiquitinated proteins and proteasomal target proteins IkB-alpha and p27, associated with proteasome inhibition, and apoptosis associated morphological changes and PARP cleavage occurred in cells treated with either Zn (PyDTC) 2 or Cu (PyDTC) 2 . We also observed that the effects of these PyDTC complexes were time-dependent, with >50% inhibition at early time points (128). To further examine the results observed with PyDTC complexes, we synthesized PyDTC:metal complexes in a 2:1 ratio (Zn (PyDTC) 2 and Cu (PyDTC) 2 ).…”

“…We determined that these synthetic complexes were much less potent toward purified 20S proteasome (40% inhibition at 50 μM), but more potent toward intact 26S proteasome in MDA-MB-231 cells, with Cu (PyDTC) 2 exhibiting higher activity than Zn (PyDTC) 2 . These synthetic complexes were also effective in other cell lines, including breast cancer DCIS and MCF7, and prostate cancer PC-3 cells (128). Additionally, partial inhibition of Cu/Zn (PyDTC) 2 -induced cell death occurred when cells were pretreated with a calpain inhibitor.…”