Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL
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ABSTRACT:
PROVIDER: PRJNA689774 | ENA |
REPOSITORIES: ENA
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Project description:Multi-agent chemotherapy still represents the first-line standard-of-care treatment for diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adults. However, the clinicopathological and molecular heterogeneity of DLBCLs poses a major challenge in their successful therapy. At least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, which differ both in their gene expression profile and in their mutation patterns, have been identified. Here we demonstrate a broad inhibitory effect of dimethyl fumarate (DMF) on the outgrowth of both DLBCL subtypes, even though the molecular basis for its efficacy differs between GCB and ABC DLBCL. Due to high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induced lipid peroxidation and thus ferroptotic cell death in GCB DLBCL. In contrast, in ABC DLBCL inhibition of NF-κB and STAT3 activity essentially contributed to DMF-dependent cytotoxicity. Interestingly, the BCL-2 specific BH3 mimetic ABT-199 or an inhibitor of the ferroptosis suppressor protein 1 synergized with DMF treatment in inducing cell death in DLBCL cell lines. Collectively, our findings identify the established and approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCL.
2021-07-01 | GSE164267 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, is characterized by an aggressive clinical course. In approximately one-third of DLBCL patients, first-line multi-agent immunochemotherapy fails to produce a durable response. Molecular heterogeneity and apoptosis resistance pose major therapeutic challenges in DLBCL treatment. To circumvent apoptosis resistance, the induction of ferroptosis might represent a promising strategy for lymphoma therapy. Here, a compound library targeting epigenetic modulators was screened to identify ferroptosis-sensitizing drugs. Strikingly, bromodomain and extra-terminal domain (BET) inhibitors sensitized cells of the germinal center B cell-like (GCB) subtype of DLBCL to ferroptosis induction and the combination of BET inhibitors with ferroptosis inducers, such as dimethyl fumarate (DMF) or RSL3, synergized in the killing of DLBCL cells in vitro and in vivo. On the molecular level, the BET protein BRD4 was found to be an essential regulator of ferroptosis suppressor protein 1 (FSP1) expression and to thus protect GCB DLBCL cells from ferroptosis. Collectively, we identified and characterized BRD4 as an important player in ferroptosis suppression in GCB DLBCL and provide a rationale for the combination of BET inhibitors with ferroptosis-inducing agents as a novel therapeutic approach for DLBCL treatment.
2023-08-01 | GSE231871 | GEO
Project description:We propose a strategy to boost the therapeutic efficacy of Oncolytic therapy by combining it with fumaric acid ester such as Dimethyl fumarate (DMF) The mechanism of action was examined by microarray analysis using the Affymetrix Human PrimeView Array.
2018-07-30 | GSE97328 | GEO
Project description:Primary human and mouse T cells were treated with the multiple sclerosis drug dimethyl fumarate (DMF) or its in vivo metabolite monomethyl fumarate (MMF). Cysteines sensitive to DMF or MMF were identified using iodoacetamide alkyne enrichment.
2016-08-31 | MSV000080111 | MassIVE
Project description:Dimethyl fumarate (DMF) is an oral drug approved for relapsing multiple sclerosis (MS) that leads to reduction of neurofilament light (NFL). This may be related to dynamics and persistence of microRNA signatures in the peripheral blood of treatment-naïve MS patients before and after dimethyl fumarate (DMF) at different time points. 210 blood samples were collected from 51 treatment-naïve patients at baseline (BL) and after 1-3, 4-7, 9-15 and 21-27 months of DMF and from 22 controls from the phase IV TREMEND trial. Using microarray, 1,085 miRNAs were two-folds above the background and compared versus NFL. Altered miRNA profiles peaked after 4-7 months. MiR-16-5p and miR-4306, involved in the NF-kB-pathway, were upregulated in low NFL samples, while miR-940 and miR-4665-3p were upregulated in high NFL samples. NFL and miRNA correlations were strongest after 4-7 months DMF. In four patients with blood samples taken at all 5 time points, time-series analysis found miR-146a-5p, the inhibitor of the NF-kB-pathway, increased 1-3 months after treatment. DMF induces dynamic changes in composite miRNA profiles 4-7 months after initiation, several involved in the NF-kB-pathway. Upregulation of miR-16-5p and miR-4306 in low-NFL, while miR-940 and miR-4665-3p in high-NFL samples may indicate a response to DMF treatment.
2022-10-26 | GSE215450 | GEO
Project description:Dimethyl fumarate (DMF) is an effective oral treatment for psoriasis administered in Europe for nearly 60 years. Its potential, however, has been limited by contact dermatitis that prohibits topical application. This paper characterizes a DMF derivative, isosorbide di-(methyl fumarate) (IDMF), which was designed to have anti-psoriatic effects without skin-sensitizing properties. We show that IDMF exhibits neither genotoxicity nor radiation sensitivity in skin fibroblasts and is non-irritating and non-sensitizing in animal models (rat, rabbit, guinea pig). Microarray analysis of cytokine-stimulated keratinocytes showed that IDMF represses the expression of genes specifically up-regulated in psoriatic skin lesions but not those of other skin diseases. IDMF also down-regulated genes induced by IL-17A and TNF in keratinocytes, as well as predicted targets of NF-κB and the anti-differentiation ncRNA (ANCR). IDMF further stimulated transcription of oxidative stress response genes (NQO1, GPX2, GSR) with stronger Nrf2/ARE activation compared to DMF. Finally, IDMF reduced erythema and scaling while repressing expression of immune response genes in psoriasiform lesions elicited by topical application of imiquimod in mice. These data demonstrate that IDMF exbibits anti-psoriatic activity that is similar or improved compared to DMF, without the harsh skin-sensitizing effects that have prevented topical delivery of the parent molecule.
2021-08-22 | GSE175473 | GEO
Project description:Dimethyl fumarate (DMF) is an effective oral treatment for psoriasis administered in Europe for nearly 60 years. Its potential, however, has been limited by contact dermatitis that prohibits topical application. This paper characterizes a DMF derivative, isosorbide di-(methyl fumarate) (IDMF), which was designed to have anti-psoriatic effects without skin-sensitizing properties. We show that IDMF exhibits neither genotoxicity nor radiation sensitivity in skin fibroblasts and is non-irritating and non-sensitizing in animal models (rat, rabbit, guinea pig). Microarray analysis of cytokine-stimulated keratinocytes showed that IDMF represses the expression of genes specifically up-regulated in psoriatic skin lesions but not those of other skin diseases. IDMF also down-regulated genes induced by IL-17A and TNF in keratinocytes, as well as predicted targets of NF-κB and the anti-differentiation ncRNA (ANCR). IDMF further stimulated transcription of oxidative stress response genes (NQO1, GPX2, GSR) with stronger Nrf2/ARE activation compared to DMF. Finally, IDMF reduced erythema and scaling while repressing expression of immune response genes in psoriasiform lesions elicited by topical application of imiquimod in mice. These data demonstrate that IDMF exbibits anti-psoriatic activity that is similar or improved compared to DMF, without the harsh skin-sensitizing effects that have prevented topical delivery of the parent molecule.
2021-08-22 | GSE175471 | GEO
Project description:Nrf2 is an important therapeutic target as activation of this pathway detoxifies harmful insults and reduces oxidative stress. However, the role of Nrf2 in cancer biology is controversial. Protection against oxidative stress and inflammation can confer a survival advantage to tumor cells, leading to a poor prognosis, and constitutive activation of Nrf2 has been detected in numerous tumors. In our study, we examined the role of two clinically relevant classes of Nrf2 activators, the synthetic triterpenoids (CDDO-Im and CDDO-Me) and dimethyl fumarate (DMF) in lung cancer. Using microarrays, we attempt to examine whether these Nrf2 activators have an effect on the same subset of Nrf2 genes.
2015-05-31 | GSE65623 | GEO
Project description:A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis
| PRJNA732447 | ENA
Project description:A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis [microarray]
| PRJNA732450 | ENA