Suppression of survival in human SKBR3 breast carcinoma in response to metal-chelator complexes is preferential for copper-dithiocarbamate.

Abstract

Since diethyl dithiocarbamate (DEDTC) forms complexes with either zinc or copper, and 8-hydroxyquinoline (8-OHQ) also complexes with copper, we now compared the cytotoxic activity of Cu[DEDTC]2, Zn[DEDTC]2 and Cu[8-OHQ]2. This report shows that at nanomolar levels, only copper-[DEDTC]2, suppresses proliferation and clonogenicity of SKBR3 human breast carcinoma, concurrently with induction of apoptosis-associated PARP fragmentation. Susceptibility to these agents was paralleled by reactive oxygen generation (ROS) and greater expression of anti-oxidant enzymes like MnSOD and catalase, with no comparable effect on Cu/Zn superoxide dismutase. The lethal effects of Cu[DEDTC]2 manifested when adding the two separate aqueous components or the preformed synthetic complexes in DMSO, was prevented by N-acetyl cysteine or glutathione, with no comparable protection afforded by non-thiol anti-oxidants like mannitol or DMSO. Exogenously added catalase also protected cells from Cu[DEDTC]2, suggesting that this complex may kill after the levels of superoxide anion [O2*-] dismutated by MnSOD increase hydrogen peroxide-related stress. Cu[DEDTC]2 also induced p21WAF1, a cdk inhibitor usually not inducible in mutant p53 tumors like SKBR3 carcinoma, correlating with dephosphorylation of the Sp1 transcription factor. Concentrations of Cu[DEDTC]2 cytotoxic for SKBR3 carcinoma did not induce comparable damage versus normal diploid human WI-38 fibroblasts. In contrast to the cytotoxic effect of nM levels of Cu[DEDTC]2 against SKBRR3 cells, no response was seen in the same cells exposed to 20 microM cis-platin. Since neither DEDTC bound to zinc, nor copper bound to 8-OHQ showed comparable cytotoxicity, our results suggest that the greater activity of copper-DEDTC reflects a specific structure-activity relationship for the active complex. Since Cu[DEDTC]2 shows more effectiveness than other metal-chelator complexes, it may be worth further investigation as an alternative to cancer therapies.

• Authors: Maricela Viola-Rhenals, Mary Strasberg Rieber, Manuel Rieber
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 71 Issue 6 Pg. 722-34 (Mar 14 2006) ISSN: 0006-2952 [Print] England
• PMID: 16412983 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2',7'-dichlorodihydrofluorescein diacetate
• Antineoplastic Agents
• Chelating Agents
• Fluoresceins
• Hydroxyquinolines
• Organometallic Compounds
• Oxyquinoline
• Copper
• Ditiocarb
• dihydroxyethyldithiocarbamate
• Zinc

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chelating Agents (chemistry, pharmacology)
• Copper (chemistry, pharmacology)
• Ditiocarb (analogs & derivatives, chemistry, pharmacology)
• Fluoresceins (metabolism)
• Humans
• Hydroxyquinolines (chemistry, pharmacology)
• Organometallic Compounds (chemistry, pharmacology)
• Oxyquinoline
• Zinc (chemistry, pharmacology)