Redox cycling by motexafin gadolinium enhances cellular response to ionizing radiation by forming reactive oxygen species

Magda, Darren; Lepp, Cheryl; Gerasimchuk, Nikolay; Lee, Intae; Sessler, Jonathan L.; Lin, Alice V.; Biaglow, John E.; Miller, Richard A.

doi:10.1016/s0360-3016(01)01810-7

Cited by 99 publications

(78 citation statements)

References 33 publications

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“…We previously reported that MGd caused an increase in radiation response in A549 cultures treated with BSO, an inhibitor of glutathione synthesis (21). This observation led us to investigate the effect of MGd treatment on the complementary, glutathione-independent thioredoxin pathway.…”

Section: Resultsmentioning

confidence: 97%

“…After 2 additional days, medium was exchanged for fresh medium (150 AL/well) supplemented with the tetrazolium dye, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma Chemical, 0.5 mg/mL). Plates were incubated at 37jC and viable cells measured as described (21). Ramos cell cultures were seeded at an initial cell density of 2.5 Â 10 5 cells/mL in 7 mL medium.…”

Section: Methodsmentioning

confidence: 99%

“…For example, motexafin gadolinium (MGd, Xcytrin, Fig. 1A), an expanded porphyrin containing the lanthanide cation gadolinium, is currently in clinical trials for the treatment of several forms of cancer (15)(16)(17)(18)(19)(20)(21)(22)(23). 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 (20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

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Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

et al. 2005

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To gain a better understanding of the mechanism of action of the metal cation-containing chemotherapeutic drug motexafin gadolinium (MGd), gene expression profiling analyses were conducted on plateau phase human lung cancer (A549) cell cultures treated with MGd. Drug treatment elicited a highly specific response that manifested in elevated levels of metallothionein isoform and zinc transporter 1 (ZnT1) transcripts. A549 cultures incubated with MGd in the presence of exogenous zinc acetate displayed synergistic increases in the levels of intracellular free zinc, metallothionein transcripts, inhibition of thioredoxin reductase activity, and cell death. Similar effects were observed in PC3 prostate cancer and Ramos B-cell lymphoma cell lines. Intracellular free zinc levels increased in response to treatment with MGd in the absence of exogenous zinc, indicating that MGd can mobilize bound intracellular zinc. These findings lead us to suggest that an important component of the anticancer activity of MGd is related to its ability to disrupt zinc metabolism and alter cellular availability of zinc. This class of compounds may provide insight into the development of novel cancer drugs targeting control of intracellular free zinc and the roles that zinc and other metal cations play in biochemical pathways relevant to cancer. (Cancer Res 2005; 65(9): 3837-45)

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Section: Resultsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

et al. 2005

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“…[1][2][3] Recent preclinical and early stage clinical trials have provided support for the notion that this gadolinium texaphyrin derivative may also have utility as a stand-alone anticancer agent. 4 One proposed mechanism of action involves the concept of redox cycling, [5][6][7] wherein a reduced texaphyrin species, formed by reaction with endogenous electron rich species such as ascorbate or glutathione, serves to form reactive oxygen species including superoxide and peroxide that are known to act as apoptosis triggering agents. [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.…”

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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“…MGd induces ROS-mediated toxicity in chemotherapy-sensitive and -resistant myeloma cell lines and in primary myeloma cells (Evens et al, 2005b). In B-cell lymphoma cell lines, MGd has been shown to sensitize cells to IR (Magda et al, 2001), disrupt intracellular zinc homeostasis by inducing metal response element-binding transcription factor-1 (MTF-1)-regulated and HIF-1-regulated genes (Lecane et al, 2005), and inhibit HMOX1 activity (Evans et al, 2007). MGd has shown single agent activity in very heavily pretreated B-chronic lymphocytic leukemia /small lymphocytic lymphoma patients, and showed complete remissions in combination with zevalin for relapsed B-cell NHL (Evens et al, 2005a).…”

Section: Arsenic Trioxide (Ato)-preclinical Data Shows Ato Activity Imentioning

confidence: 99%