title: 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 microM, which was less potent than copper(II) chloride (IC(50) 5.3 microM). 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.
authors.affiliation: The Prevention Program, Barbara Ann Karmanos Cancer Institute, Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA.
authors.forename: Vesna
authors.initials: V
authors.lastname: Milacic
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Lorena
authors.initials: L
authors.lastname: Giovagnini
authors.forename: Alejandro
authors.initials: A
authors.lastname: Diez
authors.forename: Dolores
authors.initials: D
authors.lastname: Fregona
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000633:toxicity; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D007700:Kinetics; D061988:Proteasome Inhibitors; D011759:Pyrrolidines / Q000633:toxicity*; D011817:Rabbits; D013778:Tetrazolium Salts; D013844:Thiazoles; D013859:Thiocarbamates / Q000633:toxicity*; D013997:Time Factors; D015032:Zinc / Q000737:chemistry / Q000633:toxicity
chemical_list: D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; D061988:Proteasome Inhibitors; D011759:Pyrrolidines; D013778:Tetrazolium Salts; D013844:Thiazoles; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D003300:Copper; C033668:calpastatin; D002918:Chymotrypsin; D002154:Calpain; D053148:Caspase 3; C022616:thiazolyl blue; D015032:Zinc