A physiological feature of many tumor tissues and cells is the tendency to accumulate high concentrations of copper. While the precise role of copper in tumors is cryptic, copper, but not other trace metals, is required for angiogenesis. We have recently reported that organic copper-containing compounds, including 8-hydroxyquinoline-copper(II) and 5,7-dichloro-8-hydroxyquinoline-copper(II), comprise a novel class of proteasome inhibitors and tumor cell apoptosis inducers. In the current study, we investigate whether clioquinol (CQ), an analog of 8-hydroxyquinoline and an Alzheimer's disease drug, and pyrrolidine dithiocarbamate (PDTC), a known copper-binding compound and antioxidant, can interact with copper to form cancer-specific proteasome inhibitors and apoptosis inducers in human breast cancer cells. Tetrathiomolybdate (TM), a strong copper chelator currently being tested in clinical trials, is used as a comparison. Breast cell lines, normal, immortalized MCF-10A, premalignant MCF10AT1K.cl2, and malignant MCF10DCIS.com and MDA-MB-231, were treated with CQ or PDTC with or without prior interaction with copper, followed by measurement of proteasome inhibition and cell death. Inhibition of the proteasome was determined by levels of the proteasomal chymotrypsin-like activity and ubiquitinated proteins in protein extracts of the treated cells. Apoptotic cell death was measured by morphological changes, Hoechst staining, and poly(ADP-ribose) polymerase cleavage. When in complex with copper, both CQ and PDTC, but not TM, can inhibit the proteasome chymotrypsin-like activity, block proliferation, and induce apoptotic cell death preferentially in breast cancer cells, less in premalignant breast cells, but are non-toxic to normal/non-transformed breast cells at the concentrations tested. In contrast, CQ, PDTC, TM or copper alone had no effects on any of the cells. Breast premalignant or cancer cells that contain copper at concentrations similar to those found in patients, when treated with just CQ or PDTC alone, but not TM, undergo proteasome inhibition and apoptosis. The feature of breast cancer cells and tissues to accumulate copper can be used as a targeting method for anticancer therapy through treatment with novel compounds such as CQ and PDTC that become active proteasome inhibitors and breast cancer cell killers in the presence of copper.

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Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells

Organic copper complexes as a new class of proteasome inhibitors and apoptosis inducers in human cancer cells.

Attack by reactive oxygen species leads to a decay in phycoerythrin fluorescence emission. This phenomenon provides a versatile new assay for small molecules and macromolecules that can function as protective compounds. With 1-2 x 10(-8) M phycoerythrin, under conditions where peroxyl radical generation is rate-limiting, the fluorescence decay follows apparent zero-order kinetics. On reaction with HO., generated with the ascorbate-Cu2+ system, the fluorescence decays with apparent first-order kinetics. Examination of the major components of human urine in this assay confirms that at physiological concentrations, urate protects against both types of oxygen radicals. A novel finding is that creatinine protects efficiently by a chelation mechanism against radical damage in the ascorbate-Cu2+ system at creatinine, ascorbate, and Cu2+ concentrations comparable to those in normal urine. Urate and creatinine provide complementary modes of protection against reactive oxygen species in the urinary tract.

Fluorescence-based assay for reactive oxygen species: a protective role for creatinine.

Tuning seleniumiodine contacts: from secondary soft–soft interactions to covalent bonds

Stereochemical activity of lone pairs of electrons and supramolecular aggregation patterns based on secondary interactions involving tellurium in its 1,1-dithiolate structures

Creatinine complexes of zinc, cadmium and mercury

Synthesis and crystal structure determination of the novel compound iododiethyldithiocarbamatotellurium(II)

A novel mixed ligand Te(IV) complex comprising three halides and a dithiocarbamate; synthesis and crystal structure of triiododiethyldithiocarbamatotellurium(IV), Te{(C2H5)2NCS2}I3

M.R. Udupa

Papers

Creatinine complexes of zinc, cadmium and mercury

Synthesis and crystal structure determination of the novel compound iododiethyldithiocarbamatotellurium(II)

A novel mixed ligand Te(IV) complex comprising three halides and a dithiocarbamate; synthesis and crystal structure of triiododiethyldithiocarbamatotellurium(IV), Te{(C2H5)2NCS2}I3

Preparation, characterization and cyclic voltammetric behaviour of dimeric sulphidomolybdenum(V) dithiocarbamate complexes

Synthesis and structure of the isomorphous bromo- and chlorodiethyldithiocarbamatotellurium(II), Te{(C2H5)2NCS2}X (XBr, Cl)