Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

Magda, Darren; Lecane, Philip; Miller, Richard A.; Lepp, Cheryl; Miles, Dale; Mesfin, Mimi; Biaglow, John E.; Ho, Vincent V.; Chawannakul, Danny; Nagpal, Shailender; Karaman, Mazen W.; Hacia, Joseph G.

doi:10.1158/0008-5472.can-04-4099

Cited by 59 publications

(68 citation statements)

References 55 publications

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“…In support of this, zinc administration has been shown to enhance the therapeutic indices of various antineoplastic agents (34,35). Interestingly, zinc by itself has been shown in xenograft models to be an effective antitumoral agent (36,37), as well as being implicated in the mechanism of action of novel therapies (38)(39)(40)(41). There are multiple studies suggesting that zinc addition to chemotherapeutic agents improves their antitumoral capacity, in xenograft models (20,42) as wells as in humans (43,44), and against chemoresistant cells (45).…”

Section: Discussionmentioning

confidence: 94%

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Arriaga

Greco

Mordoh

et al. 2014

Molecular Cancer Therapeutics

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Metallothioneins (MT) are a family of low molecular weight proteins that are silenced during colorectal cancer progression, mainly through epigenetic mechanisms, and this loss is associated with poor survival. In this article, we show that overexpression of the MT1G isoform sensitizes colorectal cell lines to the chemotherapeutic agents oxaliplatin (OXA) and 5-fluorouracil (5-FU), in part through enhancing p53 and repressing NF-kB activity. Despite being silenced, MTs can be reinduced by histone deacetylase inhibitors such as trichostatin A and sodium butyrate. In fact, this induction contributes to the cytotoxicity of these agents, given that silencing of MTs by siRNAs reduces their growth-inhibitory activities. Zinc ions also potently enhance MT expression and are cytotoxic to cancer cells. We show for the first time that OXA and 5-FU induce higher levels of intracellular labile zinc, as measured using the fluorescent probe FLUOZIN-3, and that such zinc contributes to the activation of p53 and repression of NF-kB. Addition of zinc enhanced growth inhibition by OXA and 5-FU, and was also capable of resensitizing 5-FU-resistant cell lines to levels comparable with sensitive cell lines. This effect was MT independent because silencing MTs did not affect zinc cytotoxicity. In conclusion, we show that MT induction and zinc administration are novel strategies to sensitize colorectal cancer cells to presently utilized chemotherapeutic agents. Mol Cancer Ther; 13(5); 1369-81. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 94%

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Arriaga

Greco

Mordoh

et al. 2014

Molecular Cancer Therapeutics

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“…[8][9][10] A similar process of electron capture followed by air-based oxidation could also contribute to the induced expression of metallothioneins and altered zinc homeostasis. 11 To the extent such redox-based modes of action are important, it provides an incentive to make and test new texaphyrin derivatives whose electronic properties are modified compared to 1. In this paper, we report the synthesis and preliminary in vitro biological analysis of a new series of gadolinium texaphyrins in which the electron-rich dialkoxydiaminobenzene derivative used in 1 is replaced by diaminonaphthalene and diaminobenzene subunits (compounds 2-5; Fig.…”

Section: Introductionmentioning

confidence: 99%

New polyethyleneglycol-functionalized texaphyrins: synthesis and in vitro biological studies

et al. 2006

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The synthesis of four new analogues of motexafin gadolinium (MGd), a gadolinium(III) texaphyrin complex in clinical trials for its anticancer properties, is described. These new derivatives contain either 1,2-diaminobenzene or 2,3-diaminonaphthalene subunits as the source of the imine nitrogens and bear multiple 2-[2-(2-methoxyethoxy)ethoxy]ethoxy (PEG) groups, on either meso aryl or beta-pyrrolic substituents, to increase their water solubility. All four analogues were found to be more active in vitro than the parent system MGd as judged from cell proliferation assays using the PC3 and A549 cell lines.

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“…Furthermore, zinc levels have been reported to modulate protein kinase C (8,9), nuclear factor nB (10,11), and p53 (12) activities and signaling pathways relevant to carcinogenesis (13,14). In light of these effects, it is perhaps not surprising that zinc possesses both antiapoptotic or proapoptotic properties that are dependent on intracellular levels (6,15).…”

Section: Introductionmentioning

confidence: 99%

“…MGd is an electron-affinic compound that mediates electron transfer from a variety of intracellular reducing species, such as ascorbate, NADPH, and thiols, to oxygen to form superoxide and hydrogen peroxide (17)(18)(19)(20). Recently, we generated gene expression profiles of plateau phase A549 lung cancer cell cultures treated with MGd and observed marked induction of transcript levels of genes that play major roles in controlling intracellular free zinc levels (6). We also reported that MGd increased intracellular free zinc levels, modulated the cellular toxicity of zinc, and inhibited cellular bioreductive activity in several human cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

Motexafin Gadolinium and Zinc Induce Oxidative Stress Responses and Apoptosis in B-Cell Lymphoma Lines

et al. 2005

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There is an emerging appreciation of the importance of zinc in regulating cancer cell growth and proliferation. Recently, we showed that the anticancer agent motexafin gadolinium (MGd) disrupted zinc metabolism in A549 lung cancer cells, leading, in the presence of exogenous zinc, to cell death. Here, we report the effect of MGd and exogenous zinc on intracellular levels of free zinc, oxidative stress, proliferation, and cell death in exponential phase human B-cell lymphoma and other hematologic cell lines. We find that increased levels of oxidative stress and intracellular free zinc precede and correlate with cell cycle arrest and apoptosis. To better understand the molecular basis of these cellular responses, gene expression profiling analyses were conducted on Ramos cell cultures treated with MGd and/or zinc acetate. Cultures treated with MGd or zinc acetate alone elicited transcriptional responses characterized by induction of metal response element-binding transcription factor-1 (MTF-1)-regulated and hypoxia-inducible transcription factor-1 (HIF-1)-regulated genes. Cultures cotreated with MGd and zinc acetate displayed further increases in the levels of MTF-1-and HIF-1-regulated transcripts as well as additional transcripts regulated by NF-E2-related transcription factor 2. These data provide insights into the molecular changes that accompany the disruption of intracellular zinc homeostasis and support a role for MGd in treatment of B-cell hematologic malignancies. (Cancer Res 2005; 65(24): 11676-88)

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Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

Cited by 59 publications

References 55 publications

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

New polyethyleneglycol-functionalized texaphyrins: synthesis and in vitro biological studies

Motexafin Gadolinium and Zinc Induce Oxidative Stress Responses and Apoptosis in B-Cell Lymphoma Lines

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