The protein thiol metallothionein as an antioxidant and protectant against antineoplastic drugs

Lazo, John S.; Kuo, Shiu‐Ming; Woo, Elizabeth S.; Pitt, Bruce R.

doi:10.1016/s0009-2797(97)00165-8

Cited by 103 publications

(81 citation statements)

References 26 publications

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“…First recognized for its singular capacity to bind intracellular Cd 2+ , attention broadened to include its interaction with other toxic metal ions, its participation in Zn 2+ and Cu metabolism, and finally the role of its manifold sulfhydryl groups in electrophile and oxidant metabolism [5,[12][13][14]. From a chemical standpoint, the properties of its unique metal ion-thiolate clusters continue to be the subject of investigation [35,36].…”

Section: Discussionmentioning

confidence: 99%

“…Yet, its facile metal ion exchange and ligand substitution reactions point toward a possible role in Zn 2+ trafficking [9][10][11]. Beyond potential activities in Zn 2+ metabolism, experimental evidence strongly supports the involvement of MT in reactions with toxic and therapeutic metals, electrophiles, and oxidants that protect cells from the deleterious effects of such reagents [12][13][14]. Considered from this perspective, the sulfhydryl reactivity of MT's 20 thiolate groups becomes of central interest.…”

Section: Introductionmentioning

confidence: 99%

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Zinc binding ligands and cellular zinc trafficking: Apo-metallothionein, glutathione, TPEN, proteomic zinc, and Zn-Sp1

Rana¹,

Kothinti²,

Meeusen³

et al. 2008

Journal of Inorganic Biochemistry

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Many cell types contain metal-ion unsaturated metallothionein (MT). Considering the Zn 2+ binding affinity of metallothionein, the existence of this species in the intracellular environment constitutes a substantial "thermodynamic sink." Indeed, the mM concentration of glutathione may be thought of in the same way. In order to understand how apo-MT and the rest of the Zn-proteome manage to co-exist, experiments examined the in vitro reactivity of Zn-proteome with apo-MT, glutathione (GSH), and a series of common Zn 2+ chelating agents including N,N,N',N'-(2-pyridylethyl) ethylenediammine (TPEN), EDTA, and [(2,2'-oxyproplylene-dinitrilo]tetraacetic acid (EGTA). Less than 10% of Zn-proteome from U87 mg cells reacted with apo-MT or GSH. In contrast, each of the synthetic chelators was 2−3 times more reactive. TPEN, a cell permeant reagent, also reacted rapidly with both Zn-proteome and Zn-MT in LLC-PK 1 cells. Taking a specific zinc finger protein for further study, apo-MT, GSH, and TPEN inhibited the binding of Zn 3 -Sp1 with its cognate DNA site (GC-1) in the sodium-glucose co-transporter promoter of mouse kidney. In contrast, preformation of Zn 3 -Sp1-(GC-1) prevented reaction with apo-MT and GSH; TPEN remained active but at a higher concentration. Whereas, Zn 3 -Sp1 is active in cells containing apo-MT and GSH, exposure of LLC-PK 1 cells to TPEN for 24 h largely inactivated its DNA binding activity. The results help to rationalize the steady state presence of cellular apo-MT in the midst of the many, diverse members of the Znproteome. They also show that TPEN is a robust intracellular chelator of proteomic Zn 2+ .

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Zinc binding ligands and cellular zinc trafficking: Apo-metallothionein, glutathione, TPEN, proteomic zinc, and Zn-Sp1

Rana¹,

Kothinti²,

Meeusen³

et al. 2008

Journal of Inorganic Biochemistry

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“…In human T cell and breast carcinoma cell lines, down-regulation of MT with antisense MT oligomers not only inhibited growth of the cells, but also activated apoptosis (Abedel-Mageed and Agrawal, 1997;Tsangaris and Tzortzatou-Stathopoulou, 1998). In studies using tumour cell lines, it was found that tumour cells with a high expression of MT were more resistant against the toxic effects of anticancer agents such as cisplatin as well as radiation exposure (Kondo et al, 1995;Lazo et al, 1998). In addition, in both human primary hepatocellular carcinoma and metastatic carcinoma, the MT levels were low and had higher number of apoptotic cells as compared to normal liver (Cai et al, 1998;Deng et al, 1998).…”

mentioning

confidence: 99%

Potential role of p53 on metallothionein induction in human epithelial breast cancer cells

Fan

Cherian

2002

Br J Cancer

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The expression and induction of metallothionein has been associated with protection against oxidative stress and apoptosis. This study examines the effect of tumour suppressor protein p53 on metallothionein expression following CdCl 2 treatment in eight human epithelial breast cancer cell lines differing in p53 and oestrogen-receptor status. Cells were treated with 10 mM CdCl 2 for 24 h and metallothionein protein levels were measured by cadmium binding assay. MCF7 cells which are p53-positive (p53+) and oestrogen-receptor-positive showed a large induction in metallothionein synthesis by 10.79+1.36-fold. Other breast cancer cell lines which are p53-negative (p537) and oestrogen-receptor-negative or weakly oestrogenreceptor-positive showed a small induction ranging from 1.40+0.10 to 3.65+0.30-fold. RT -PCR analysis showed an induction of metallothionein mRNA in MCF7 cells by about 1.61+0.08-fold, while in HCC1806 cells (p537, oestrogenreceptor-negative) by 1.11+0.13-fold, and in MDA-MB-231 (p537, oestrogen-receptor-negative) by 1.25+0.06-fold. Metallothionein localisation was determined by immunohistochemical staining. Prior to metal treatment, metallothionein was localised mainly in the cytoplasm of MCF7 and MDA-MB-231 cells. After treatment with 10 mM CdCl 2 for 24 h, MCF7 cells showed intense nuclear and cytoplasmic staining for metallothionein, while MDA-MB-231 cells showed staining in the cytoplasm with weak nuclear staining. Apoptosis induced by 10 -40 mM CdCl 2 at time points between 4 and 48 h was examined with TUNEL assay. In MCF7 cells, apoptosis increased with higher concentrations of CdCl 2 , it peaked at 6 -8 h and appeared again at 48 h for all concentrations of CdCl 2 tested. In MDA-MB-231 cells, apoptosis remained at low levels for 10 -40 mM CdCl 2 at all time points. Studies on cadmium uptake showed similar uptake and accumulation of cadmium at 8 and 24 h in all the cell lines. The data demonstrate that treatment of epithelial breast cancer cells with 10 mM CdCl 2 for 24 h caused a greater induction of metallothionein protein and mRNA expression in p53+ and oestrogen-receptor-positive cells as compared to p537 and oestrogen-receptor-negative or weakly oestrogen-receptor-positive cells. This effect may be associated with the occurrence of apoptosis and suggests a role for p53 and oestrogen-receptor on the expression and induction of metallothionein in epithelial cells.

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“…The physiologic roles of MT-I+II are not fully elucidated however, data describing MT-I+II as tissue protective factors are accumulating (Aschner, 1996(Aschner, ,1997Aschner et al, 1997;Kondo et al, 1997;Lazo et al ,1998Liu et al, 1999;Penkowa et al, 1999a,b;Rossman et al, 1997;Schwarz et al, 1995;Van Lookeren Campagne et al, 1999). MT-I+II can protect against reactive oxygen species causing oxidative damage and stress, ionizing radiation, anti-cancer drugs, and interestingly, MT-I+II may prevent neuronal apoptosis (Aschner, 1998;Lazo et al, ,1998Penkowa et al, 1999aPitt et al, 1997;Schwarz et al, 1995;Tamai et al, 1993;Thornalley and Vasak, 1985).…”

mentioning

confidence: 99%

“…MT-I+II can protect against reactive oxygen species causing oxidative damage and stress, ionizing radiation, anti-cancer drugs, and interestingly, MT-I+II may prevent neuronal apoptosis (Aschner, 1998;Lazo et al, ,1998Penkowa et al, 1999aPitt et al, 1997;Schwarz et al, 1995;Tamai et al, 1993;Thornalley and Vasak, 1985).…”

mentioning

confidence: 99%

Altered Central Nervous System Cytokine-Growth Factor Expression Profiles and Angiogenesis in Metallothionein-I+II Deficient Mice

Penkowa

Carrasco

Giralt

et al. 2000

J Cereb Blood Flow Metab

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Summary:To study the importance of metallothionein-I and -II (MT-I+II) for brain inflammation and regeneration, the authors examined normal and MT-I+II knock-out (MT-KO) mice subjected to a cortical freeze injury. Normal mice showed profound neurodegeneration, inflammation, and gliosis around the injury, which was repaired by 20 days postlesion (dpl). However, in MT-KO mice the lesion-associated inflammation was still present as late as 90 dpl. Scanning electron microscopy demonstrated that the number of capillaries was lower, and ultrastructural preservation of the lesioned parenchyma was poorer in MT-KO mice, suggesting an altered angiogenesis. To gain insight into the mechanisms involved, a number of cytokines and growth factors were evaluated. The number of cells expressing the proinflammatory cytokines IL-1␤, IL-6, and TNF-␣ was higher in MT-KO mice than in normal mice, which was confirmed by RNase protection analysis, whereas the number of cells expressing the growth factors bFGF, TGF␤1, VEGF, and NT-3 was lower. Increased expression of proinflammatory cytokines could be involved in the sustained recruitment of CD-14+ and CD-34+ inflammatory cells and their altered functions observed in MT-KO mice. Decreases in trophic factors bFGF, TGF␤1, and VEGF could mediate the decreased angiogenesis and regeneration observed in MT-KO mice after the freeze lesion. A role for MT-I+II in angiogenesis was also observed in transgenic mice expressing IL-6 under the control of the promoter of glial fibrillary acidic protein gene (GFAP-IL6 mice) because MT-I+II deficiency dramatically decreased the IL-6-induced angiogenesis of the GFAP-IL6 mice. In situ hybridization analysis indicated that the MT-III expression was not altered by MT-I+II deficiency. These results suggest that the MT-I+II isoforms have major regulatory functions in the brain inflammatory response to injury, especially in the angiogenesis process. Key Words: MT-I+II-MT-IIIInflammation-Angiogenesis-Regeneration-Cytokines.Metallothioneins are a family of cysteine-rich, ubiquitous intracellular proteins. In the central nervous system (CNS), MT-I+II are expressed coordinately and are increased in macrophages/microglia and astrocytes during various inflammatory and pathologic conditions, including human neurodegenerative disorders, experimentally induced brain injury, epileptic seizures, brain ischemia, astroglial cell death, metal exposure, stress, and myelin deficiency

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The protein thiol metallothionein as an antioxidant and protectant against antineoplastic drugs

Cited by 103 publications

References 26 publications

Zinc binding ligands and cellular zinc trafficking: Apo-metallothionein, glutathione, TPEN, proteomic zinc, and Zn-Sp1

Zinc binding ligands and cellular zinc trafficking: Apo-metallothionein, glutathione, TPEN, proteomic zinc, and Zn-Sp1

Potential role of p53 on metallothionein induction in human epithelial breast cancer cells

Altered Central Nervous System Cytokine-Growth Factor Expression Profiles and Angiogenesis in Metallothionein-I+II Deficient Mice

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