Suppression of survival in human SKBR3 breast carcinoma in response to metal-chelator complexes is preferential for copper-dithiocarbamate.
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.
Viola-Rhenals
Maricela
M
Instituto Venezolano de Investigaciones Cientificas, IVIC, Centre for Microbiology & Cell Biology, Laboratory of Tumor Cell Biology, Apartado 21827, Caracas 1020 A, Venezuela. mviola@ivic.ve
Rieber
Mary Strasberg
MS
Rieber
Manuel
M
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D015125:Oxyquinoline; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology
C110400:2',7'-dichlorodihydrofluorescein diacetate; D000970:Antineoplastic Agents; D002614:Chelating Agents; D005452:Fluoresceins; D006912:Hydroxyquinolines; D009942:Organometallic Compounds; D015125:Oxyquinoline; D003300:Copper; D004050:Ditiocarb; C039353:dihydroxyethyldithiocarbamate; D015032:Zinc