Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tak1-inhibitors are cytotoxic for multiple myeloma cells alone and in combination with melphalan

ABSTRACT: To determine which genes are affected by NG25 and melphalan, we performed an RNA-seq on INA-6 cells treated with NG25, melphalan or a combination of the two. GSEA focusing on the hallmark pathways showed that melphalan-treatment upregulated genes involved in UV-response, DNA-repair, p53-pathway and TNF-signaling via NF-kB. NG25 induced expression of genes involved in cholesterol homeostasis and mTORC1-signaling and down-regulated MYC- and E2F-targets. MYC is a central driver of MM pathology, and regulate survival as well as cell cycle control through E2F. NG25 reversed the melphalan-induced UV-response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178292 | GEO | 2021/06/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Tak1-inhibitors are cytotoxic for multiple myeloma cells alone and in combination with melphalan

Project description:Tak1-inhibitors are cytotoxic for multiple myeloma cells alone and in combination with melphalan

| PRJNA738364 | ENA

TAK1-inhibitors are cytotoxic for multiple myeloma cells alone and in combination with melphalan.

Project description:Multiple myeloma (MM) is an incurable cancer caused by malignant transformation of plasma cells. Transforming growth factor-β activated kinase 1 (MAP3K7, TAK1) is a major regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. Both NF-κB and MAPK control expression of genes with vital roles for drug resistance in MM. TAK1 is an attractive drug target as it switches these survival pathways to cell death. Our analysis showed that patients with high MAP3K7 expression in the tumor had shorter overall and progression free survival. The TAK1-inhibitors NG25 and 5Z-7-oxozeaenol (5Z-7) were cytotoxic to MM cell lines and patient cells. NG25 reduced expression of MYC and E2F controlled genes, involved in tumor cell growth, cell cycle progression and drug resilience. TAK1 can be activated by genotoxic stress. NG25 and 5Z-7 induced both synergistic and additive cytotoxicity in combination with the alkylating agent melphalan. Melphalan activated TAK1, NF-κB, and the MAPKs p38 and c-Jun N-terminal kinase (JNK), as well as a transcriptional UV-response. This was blocked by NG25, and instead apoptosis was activated. MM induce elevated bone-degradation resulting in myeloma bone disease (MBD), which is the main cause of disability and morbidity in MM patients. NG25 and 5Z-7 reduced differentiation and viability of human bone degrading osteoclasts, suggesting that TAK1-inhibition can have a double beneficial effect for patients. In sum, TAK1 is a promising drug target for MM treatment.

| S-EPMC8522844 | biostudies-literature

Metabolic Changes Contribute to Melphalan Resistance in Multiple Myeloma

Project description:Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the U.S. Treatment for eligible patients includes three stages: induction, consolidation with stem cell rescue, and maintenance. High dose therapy with the DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem cell transplant. As a result, melphalan resistance remains a clinical challenge. Here, we use proteometabolomics to examine mechanisms of melphalan resistance in two cell line models. Drug metabolism, steady-state metabolomics, activity-based protein profiling (ABPP), acute treatment metabolomics, and immunoblotting analyses have allowed us to further elucidate metabolic processes contributing to melphalan resistance. Proteometabolomics data indicate that both drug resistant cells have higher levels of pentose phosphate pathway metabolites than their naïve counterparts. Interestingly, we also observed cell line specific changes in purine, pyrimidine and glutathione metabolism that are linked to the differences in steady state metabolism of naïve cells and highlight the heterogeneity of melphalan resistance in these models. Because of the diversity of metabolic changes, our data suggest that omics approaches will be needed to fully examine melphalan resistance in patient specimens and define personalized strategies to optimize the delivery of this therapy.

2020-07-17 | PXD019725 | Pride

Melphalan-treated human retinal endothelial cells

Project description:Super-selective intra-ophthalmic artery chemotherapy (SSIOAC) is an organ-specific drug-delivery strategy to treat retinoblastoma, the most common primary ocular malignancy in children. Unfortunately, recent clinical reports associate adverse vascular toxicities with SSIOAC using melphalan, the most commonly used chemotherapeutic. To explore the reason for the unexpected vascular toxicities, we have developed in vitro studies with human retinal endothelial cells to test the effects of the chemotherapeutics and a non-human primate model to monitor the SSIOAC treatment in real-time and post-treatment. Melphalan and carboplatin (another chemotherapeutic used to treat retinoblastoma via SSIOAC) triggered migration, proliferation, and apoptosis when used to treat human retinal endothelial cells. Melphalan was associated with increased adhesion of leukocytes to human retinal endothelial cells, and tended to increase with increased cell expression of adhesion proteins (ICAM-1) and soluble chemotactic factors (IL-8). Histopathology post-SSIOAC indicated vessel wall sloughing, leukostasis, and vessel occlusion. We have established an in vitro human cell culture model and a non-human primate model to evaluate strategies designed to obviate vascular side effects, and optimize the efficacy of SSIAOC and the drug preparations used in SSIOAC. 4 non-treated (MNT) vs. 4 melphalan-treated primary human retinal endothelial cells (RECs).

2011-12-13 | E-GEOD-34381 | biostudies-arrayexpress

Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

Project description:Multiple myeloma RPMI8226 cells adapted to growth in melphalan display a shift towards Warburg metabolism and modulated oxidative stress signaling. Inhibitors targeting specific enzymes in these pathways are selectively toxic to the melphalan-resistant cells. To investigate large scale alterations in gene expression accompanying melphalan resistance, we used the multiple myeloma cell line RPMI8226 and its melphalan-resistant derivative LR5. The stable isotope labeling by amino acids in cell culture (SILAC) approach.

2015-05-26 | PXD001276 | Pride

In vivo study of ADH-1 in combination with melphalan for treatment of melanoma

Project description:To identify patterns of change in gene expression that correlated with drug treatment (saline control, ADH-1 alone, melphalan alone and ADH-1 plus melphalan) in our animal model of regional therapy for extremity melanoma we evaluated gene expression using microarray genechips and a Pearson correlation analysis. Genes were ranked according to the degree to which expression correlated with systemic ADH-1 treatment alone or in combination with regional melphalan. Tissue samples were harvested at 4, 24 and 48 hours after treatment with melphalan. Specific cellular pathways associated with drug treatment were identified using gene set enrichment analysis (GSEA). Keywords: time course; chemotherapy; melanoma; melphalan; N-cadherin; ADH-1

2008-10-30 | GSE8615 | GEO

Melphalan-treated human retinal endothelial cells

2011-12-13 | GSE34381 | GEO

Protective effects on melphalan-induced mouse intestinal injury treated by Human Umbilical Cord-derived Mesenchymal Stem Cells

Project description:Autologous peripheral hematopoietic stem cell transplantation (autoHSCT) is one front-line therapy with high-dose melphalan for multiple myeloma (MM). Patients with MM who receive conditioning regimen with melphalan usually suffer from severe gastrointestinal symptoms, as one of nonhematological toxicities. Aim: It is an urgent demand to develop an effective methods to repair the intestinal injuries in patients with MM receiving conditioning regimen with high-dose melphalan for autoHSCT. Therefore, the protective effects of Human umbilical cord derived-mesenchymal stem cells (hucMSCs) is investigated after infusion into mouse model with melphalan-induce gastrointestinal injuries.

2024-04-01 | GSE225899 | GEO

T-cells' gene expression after high-dose melphalan

Project description:T-cells' transduction efficacy by lentiviral transduction is diminished after high-dose melphalan. To investigate transcriptional changes regarding genes inhibiting viral entry, reverse transcription, nuclear transport and viral genome integration, we performed microarray transcription analysis.

2020-11-23 | GSE148770 | GEO

Dll4iDEC mouse liver endothelial cells

Project description:Myc and its target Odc1 were among the most 250 strongly upregulated genes in Dll4 mutant ECs, compared with Notch1 and Rbpj mutants. Myc is known to activate important ribosome biogenesis and protein translation pathways, favoring cell growth. Dll4iDEC livers showed upregulation of a large range of canonical E2F, Myc, and mTORC1 target genes and ribosomal genes, particularly in the activated, proliferating, and endothelial tip-cell clusters. This hypermetabolic transcriptional status was confirmed by in-depth proteomics analysis of protein lysates obtained from freshly isolated liver ECs, providing the first proteomics analysis of the endothelial tip-cell state induced by targeting Dll4.

2023-04-11 | PXD041349 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data