Tak1-inhibitors are cytotoxic for multiple myeloma cells alone and in combination with melphalan
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ABSTRACT:
PROVIDER: PRJNA738364 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14827318.fastq.gz | Fastqsanger.gz | |||
| SRR14827319.fastq.gz | Fastqsanger.gz | |||
| SRR14827320.fastq.gz | Fastqsanger.gz | |||
| SRR14827321.fastq.gz | Fastqsanger.gz | |||
| SRR14827322.fastq.gz | Fastqsanger.gz |
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Project description: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.
2021-06-17 | GSE178292 | GEO
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
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
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). Experiment Overall Design: Sample size was 2 rats for each drug treatment group at both the 4 and 24 hour time points. At the 48 hour time point sample size was 1 rat for each drug treatment group. ADH-1 treatment preceded melphalan by 1 hour. ADH-1 treatment was repeated at 24 and 48 hrs. Tissue was harvested for RNA analysis at 4, 24 and 48 hours after completion of isolated limb infusion with melphalan (and 1 hour after an ADH-1 dose).
2008-11-07 | E-GEOD-8615 | biostudies-arrayexpress
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
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
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.
2014-09-03 | GSE60970 | GEO
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. The gene expression profiles were measured on 6 batches each of control and melphalan-treated RPMI8226 and RPMI8226-LR5 cells using Illumina Human HT-12 v3 Expression BeadChip (Illumina, San Diego, CA), which enables genome-wide expression analysis (more than 47 000 transcripts) of 24 samples in parallel on a single microarray.
2014-09-03 | E-GEOD-60970 | biostudies-arrayexpress
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
Project description:Background Toxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis. Methods and Findings Ten patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration. We also acquired buccal biopsies from 10 healthy individuals that served as controls. We analyzed the biopsies for global gene expression and performed an immunohistochemical analysis to determine HLA-DRB5 expression. We evaluated associations between clinical mucositis and gene expression profiles. Compared to gene expression levels before and 20 days after therapy, at two days after melphalan treatment, we found gene regulation in the p53 and TNF pathways (MDM2, INPPD5, TIGAR), which favored anti-apoptotic defense, and upregulation of immunoregulatory genes (TREM2, LAMP3) in mucosal dendritic cells. This upregulation was independent of clinical mucositis. HLA-DRB1 and HLA-DRB5 (surface receptors on dendritic cells) were expressed at low levels in all patients with MM, in the subgroup of patients with ulcerative mucositis (UM), and in controls; in contrast, the subgroup with low-grade mucositis (NM) displayed 5–6 fold increases in HLA-DRB1 and HLA-DRB5 expression in the first two biopsies, independent of melphalan treatment. Moreover, different splice variants of HLA-DRB1 were expressed in the UM and NM subgroups. Conclusions Our results revealed that, among patients with MM, immunoregulatory genes and genes involved in defense against apoptosis were affected immediately after melphalan administration, independent of the presence of clinical mucositis. Furthermore, our results suggested that the expression levels of HLA-DRB1 and HLA-DRB5 may serve as potential predictive biomarkers for mucositis severity
2016-12-19 | GSE81979 | GEO