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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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LMP-420: a novel purine nucleoside analogue with potent cytotoxic effects for chronic lymphocytic leukemia cells

ABSTRACT: [original title] LMP-420: a novel purine nucleoside analogue with potent cytotoxic effects for chronic lymphocytic leukemia cells and minimal toxicity for normal hematopoietic cells. LMP-420 induces cytotoxicity and apoptosis to CLL cells in vitro without any negative effects to normal immune cells. This gene expression experiment compares CLL cells treated with LMP-420 versus media alone to investigate the mechanism of action of LMP-420. CLL cells from 13 patients were treated with LMP-420 or media for 24 hours, then RNA was extracted and assayed on U133Plus2 GeneChips.

ORGANISM(S): Homo sapiens

SUBMITTER: Daphne Friedman

PROVIDER: E-GEOD-20211 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells.

Mowery Y M YM Weinberg J B JB Kennedy M N MN Bond K M KM Moore J O JO Lanasa M C MC Gockerman J P JP Diehl L F LF Pizzo S V SV Cianciolo G J GJ Friedman D R DR

Leukemia 20100708 9

B-cell chronic lymphocytic leukemia (CLL) is characterized by slow accumulation of malignant cells, which are supported in the microenvironment by cell-cell interactions and soluble cytokines such as tumor necrosis factor (TNF). We evaluated the effect of the small molecule TNF inhibitor LMP-420 on primary CLL cells. The mean concentration of LMP-420 required to induce 50% cytotoxicity (ED50) at 72 h was 245 n. LMP-420-induced time- and dose-dependent apoptosis, as shown by annexin V staining, c ...[more]

PMID: 20613784

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LMP-420: a novel purine nucleoside analogue with potent cytotoxic effects for chronic lymphocytic leukemia cells

Project description:[original title] LMP-420: a novel purine nucleoside analogue with potent cytotoxic effects for chronic lymphocytic leukemia cells and minimal toxicity for normal hematopoietic cells. LMP-420 induces cytotoxicity and apoptosis to CLL cells in vitro without any negative effects to normal immune cells. This gene expression experiment compares CLL cells treated with LMP-420 versus media alone to investigate the mechanism of action of LMP-420.

2011-02-01 | GSE20211 | GEO

Transition state analogue discrimination by related purine nucleoside phosphorylases.

Project description: Not available

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Project description:LMP-420: a novel purine nucleoside analogue with potent cytotoxic effects for chronic lymphocytic leukemia cells

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Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity

Project description:Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with down-regulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a novel metabolic immune checkpoint.

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Project description: Not available

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The search for enzymes responsible for metabolism of nucleoside analogs

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2005-10-30 | GSE1862 | GEO

Chemosensitization of DLBCL cells in vitro and in vivo by demethylating nucleoside analogues

Project description:This SuperSeries is composed of the following subset Series: GSE28744: Chemosensitization of DLBCL cells in vitro and in vivo by demethylating nucleoside analogues [gene expression] GSE31101: Chemosensitization of DLBCL cells in vitro and in vivo by demethylating nucleoside analogues [methylation] Refer to individual Series. Supplementary file [gene expression]: To better approach the delta analysis and find differences between sensitive cell lines and resistant cell lines to doxorubicin, we filtered the gene expression matrix for probes with a greater standard deviation among all samples greater than 0.5. We therefore kept 11842 probesets that we used for the analysis.

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Nucleoside Analogues are Potent Inducers of Bacterial Mutagenesis

Project description:Drugs targeting DNA and RNA in mammalian cells or viruses can also affect bacteria present in the host and thereby induce the bacterial SOS system. This has the potential to increase mutagenesis and the development of antimicrobial resistance (AMR). Here we have examined nucleoside analogues (NAs) commonly used in anti-viral and anti-cancer therapies for potential effects on mutagenesis in Escherichia coli using the Rifampicin mutagenicity assay. To further explore the mode of action of the NAs, we appliedanalyzed metabolome and proteome of E.coli deletion mutants., and metabolome and proteome analyses. Five out of the thirteen NAs examined, including three nucleoside reverse transcriptase inhibitors (NRTIs) and two anti-cancer drugs, increased the mutation frequency in E. coli more than 25-fold at doses that were within reported plasma concentration range (Pl.CR), but that did not affect bacterial growth. We show that the SOS response is induced and that the increase in mutation frequency is mediated by the TLS polymerase Pol V. Quantitative mass spectrometry based metabolite profiling did not reveal large changes in nucleoside phosphate or other central carbon metabolite pools, which suggests that the SOS induction is an effect of increased replicative stress. Our results suggest that NAs/NRTIs can contribute to the development of AMR.

2021-07-15 | PXD025370 | Pride

Dual protein kinase/ nucleoside kinase modulat ors for rationally designed polypharmacology

Project description:Masitinib, a highly selective protein kinase inhibitor, can sensitise gemcitabine-refractory cancer cell lines when used in combination with gemcitabine. A reverse proteomic approach has identified the target responsible for this sensitisation: the deoxycytidine kinase (dCK). Masitinib, as well as other protein kinase inhibitors such as imatinib, interact with dCK and provoke an unforeseen conformational-dependent activation of this nucleoside kinase, modulating phosphorylation of nucleoside analogue drugs. This phenomenon leads to an increase of prodrug phosphorylation of most of the chemotherapeutic drugs activated by this nucleoside kinase. The unforeseen dual activity of protein kinase inhibition/nucleoside kinase activation could be of great therapeutic benefit, through either reducing toxicity of therapeutic agents by maintaining effectiveness at lower doses or by counteracting drug resistance initiated via down modulation of dCK target.

2017-11-13 | PXD007765 | Pride

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