Glutamate antagonists limit tumor growth

Rzeski, Wojciech; Turski, Lechosław; Ikonomidou, Chrysanthy

doi:10.1073/pnas.091113598

Cited by 247 publications

(179 citation statements)

References 38 publications

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“…20 Moreover, as opposed to bilirubin-mediated neuronal cell death, which is triggered by stimulation of the NMDA receptor 66 and prevented by NMDA receptor antagonists, 22 both glutamate and NMDA inhibitors reduce the viability of HT29 adenocarcinoma cells. 67 These disparities in the cellular response may be a result of nonphysiologic concentrations of bilirubin utilized or, alternatively, may reflect distinct mechanisms of bilirubin action in different cell lines. In support of the latter hypothesis are reports of differing sensitivities of neural cells to bilirubin cytotoxicity.…”

Section: Effect Of Bilirubin On the Permeability Of Isolated Mitochonmentioning

confidence: 99%

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

Keshavan¹,

Schwemberger²,

Smith³

et al. 2004

Intl Journal of Cancer

113

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Bilirubin is the principal end product of heme degradation. Prompted by epidemiologic analyses demonstrating an inverse correlation between serum bilirubin levels and cancer mortality, we examined the effect(s) of bilirubin on the growth and survival of colon adenocarcinoma cells. Adenocarcinoma cell monolayers were treated with bilirubin over a range of bilirubin:BSA molar ratios (0 -0.6), and viability was assessed colorimetrically. Apoptosis was characterized by TUNEL assay, annexin V staining and caspase-3 activation. The mechanism(s) by which bilirubin induces apoptosis was investigated by Western blotting for cytochrome c release, assaying for caspase-8 and caspase-9 activation and for mitochondrial depolarization by JC-1 staining. The direct effect of bilirubin on the membrane potential of isolated mitochondria was evaluated using light-scattering and fluorescence techniques. Bilirubin decreased the viability of all colon cancer cell lines tested in a dose-dependent manner. Cells exhibited substantial apoptosis when exposed to bilirubin concentrations ranging 0 -50 M, as demonstrated by an 8-to 10-fold increase in TUNEL and annexin V staining and in caspase-3 activity. Bilirubin treatment evokes specific activation of caspase-9, enhances cytochrome c release into the cytoplasm and triggers the mitochondrial permeability transition in colon cancer monolayers. Additionally, bilirubin directly induces the depolarization of isolated rat liver mitochondria, an effect that is not inhibited by cyclosporin A. Bilirubin stimulates apoptosis of colon adenocarcinoma cells in vitro through activation of the mitochondrial pathway, apparently by directly dissipating mitochondrial membrane potential. As this effect is triggered at concentrations normally present in the intestinal lumen, we postulate a physiologic role for bilirubin in modulating colon tumorigenesis.

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Section: Effect Of Bilirubin On the Permeability Of Isolated Mitochonmentioning

confidence: 99%

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

Keshavan¹,

Schwemberger²,

Smith³

et al. 2004

Intl Journal of Cancer

113

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“…Cells were also exposed to 50 ng of p21 small interfering RNA (siRNA) per well, diluted in GeneSilencer reagent, or exposed to GeneSilencer reagent (Gene Therapy Systems, San Diego) in growing medium with 10% FCS, according to the manufacturer's protocol. Cell proliferation was assessed after 48 -96 h by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide method (14).…”

Section: Methodsmentioning

confidence: 99%

NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth

Stepulak

Sifringer²,

Rzeski³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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132

118

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“…PDB codes: glutamate (1ftj), AMPA (1ftm), quisqualate (zinc, 1mm7; no zinc, 1mm6), kainate (1fwo), fluorowillardiine (1mqi), bromowillardiine (zinc, 1my3; no zinc, 1mqh), iodowillardiine (zinc, 1my4; no zinc, 1mqg), DNQX (1ftl), apo (1fto). The peptide flip is shown as a question mark for fluorowillardiine because the one crystal structure is unflipped, but HD exchange studies 3 suggest that the hydrogen bond, suggestive of the flipped conformation, is present in solution. Although the apo form is given as unflipped, as suggested by the two crystal structures, the dynamic nature of this form would suggest that an equilibrium between the flipped and unflipped forms cannot be ruled out.…”

Section: Table 1 Relaxation Parameters (Ms)mentioning

confidence: 99%

“…In addition, ionotropic GluRs have been implicated in various neurodegenerative disorders such as Parkinson and Alzheimer diseases, Huntington chorea, and neurologic disorders including epilepsy and ischemic brain damage. Antagonists of glutamate receptors have been shown to limit tumor growth in a variety of human tumors and to inhibit tumor cell migration (3). In recent years many advances in characterizing the relationship between ionotropic GluR structure and function have been made.…”

mentioning

confidence: 99%

Dynamics of the S1S2 Glutamate Binding Domain of GluR2 Measured Using 19F NMR Spectroscopy

Ahmed

Loh

Jane

et al. 2007

Journal of Biological Chemistry

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Ionotropic glutamate receptors mediate the majority of vertebrate excitatory synaptic transmission. Although the structure of the GluR2 binding domain (S1S2) is well known (agonist binding site between two lobes), little is known about the time scales of conformational transitions or the relationship between dynamics and function.19 F NMR ( 19 F-labeled tryptophan) spectroscopy was used to monitor motions in the S1S2 domain bound to ligands with varying efficacy and in the apo state. One tryptophan (Trp-671) undergoes chemical exchange in some but not all agonists, consistent with s-ms motion. The dynamics can be correlated to ligand affinity, and a likely source of the motion is a peptide bond capable of transiently forming hydrogen bonds across the lobe interface. Another tryptophan (Trp-767) appears to monitor motions of the relative positions of the lobes and suggests that the relative orientation in the apo-and antagonist-bound forms can exchange between at least two conformations on the ms time scale. Ionotropic glutamate receptors (GluRs)2 mediate the majority of excitatory synaptic transmission in the central nervous system of higher vertebrates (1) and play important roles in the formation of synaptic plasticity underlying higher order processes such as learning and memory as well as in neuronal development (2). In addition, ionotropic GluRs have been implicated in various neurodegenerative disorders such as Parkinson and Alzheimer diseases, Huntington chorea, and neurologic disorders including epilepsy and ischemic brain damage. Antagonists of glutamate receptors have been shown to limit tumor growth in a variety of human tumors and to inhibit tumor cell migration (3). In recent years many advances in characterizing the relationship between ionotropic GluR structure and function have been made. Ionotropic GluRs are membrane-bound receptor ion channels composed of multiple subunits arranged as a rosette, forming a central ion channel in which each subunit contributes to pore formation. Individual subunits are categorized by pharmacological properties, sequence, functionality, and biological roles into those that are sensitive 1) to the synthetic agonist N-methyl-D-aspartic acid (NR1, NR2A-D, NR3A-B), 2) to the synthetic agonist ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; GluR1-4), and 3) to the naturally occurring neurotoxin kainate (GluR5-7, KA1,2).The structural analysis of glutamate receptors was dramatically advanced by the finding that the extracellular agonist binding domain (S1S2 domain) could be expressed in isolation as a soluble protein (4) and by the subsequent solution of the crystal structure bound to kainate (5). As predicted by homology models (6), the S1S2 domain was found to be a bilobed structure with the agonist binding pocket located between the two lobes. The first glimpse of the structural basis of channel activation was the finding by Armstrong and Gouaux (7) that the apo state exhibited a considerably larger angle between the two lobes than the full agonist-bound...

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Glutamate antagonists limit tumor growth

Cited by 247 publications

References 38 publications

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth

Dynamics of the S1S2 Glutamate Binding Domain of GluR2 Measured Using 19F NMR Spectroscopy

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