Regulation of dimethyl-fumarate toxicity by proteasome inhibitors

Booth, Laurence; Cruickshanks, Nichola; Tavallai, Seyedmehrad; Roberts, Jeanette C.; Peery, Matthew; Poklepovic, Andrew; Dent, Paul

doi:10.4161/15384047.2014.967992

Cited by 26 publications

(33 citation statements)

References 46 publications

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“…Recent reports have shown that NRF2 regulates ER stress‐induced cell death in multiple myeloma, possibly via the proteasome machinery, which degrades damaged and misfolded proteins; suggesting that DMF might be used to target ER proteins via NRF2. Furthermore, in vitro experiments on glioblastoma cells suggest that inhibition of the eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4) arm of the ER stress response enhances the lethality of MMF, either alone or in combination with proteasome inhibitors; and this effect is associated with increased ROS production leading to cell death. Phosphorylation of eIF2α plays an important role in the ER stress response as it attenuates global protein translation, thereby, allowing cells to recover from the accumulation of unfolded proteins.…”

Section: Toward Personalized Cancer Therapy: Cancer Dependent Of Nrf2mentioning

confidence: 99%

“…Finally, DMF can alter the redox system of cells by directly targeting microtubules such as tubulin. DMF inhibits free sulfhydryls in tubulin 27 and possibly interferes with spindle assembly leading to cell cycle arrest and apoptosis enhances the lethality of MMF, either alone or in combination with proteasome inhibitors 129 ; and this effect is associated with increased ROS production leading to cell death. Phosphorylation of eIF2α plays an important role in the ER stress response as it attenuates global protein translation, thereby, allowing cells to recover from the accumulation of unfolded proteins.…”

Section: Er Proteinsmentioning

confidence: 99%

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Dimethyl fumarate, a two‐edged drug: Current status and future directions

Saidu

Kavian

Leroy

et al. 2019

Medicinal Research Reviews

120

100

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Dimethyl fumarate (DMF) is a fumaric acid ester registered for the treatment of relapsing‐remitting multiple sclerosis (RRMS). It induces protein succination leading to inactivation of cysteine‐rich proteins. It was first shown to possess cytoprotective and antioxidant effects in noncancer models, which appeared related to the induction of the nuclear factor erythroid 2 (NF‐E2)–related factor 2 (NRF2) pathway. DMF also displays antitumor activity in several cellular and mice models. Recently, we showed that the anticancer mechanism of DMF is dose‐dependent and is paradoxically related to the decrease in the nuclear translocation of NRF2. Some other studies performed indicate also the potential role of DMF in cancers, which are dependent on the NRF2 antioxidant and cellular detoxification program, such as KRAS‐mutated lung adenocarcinoma. It, however, seems that DMF has multiple biological effects as it has been shown to also inhibit the transcription factor nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), thus blocking downstream targets that may be involved in the development and progression of inflammatory cascades leading to various disease processes, including tumors, lymphomas, diabetic retinopathy, arthritis, and psoriasis. Herein, we present the current status and future directions of the use of DMF in various diseases models with particular emphases on its targeting of specific intracellular signal transduction cascades in cancer; to shed some light on its possible mode of action.

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Section: Toward Personalized Cancer Therapy: Cancer Dependent Of Nrf2mentioning

confidence: 99%

Section: Er Proteinsmentioning

confidence: 99%

Dimethyl fumarate, a two‐edged drug: Current status and future directions

Saidu

Kavian

Leroy

et al. 2019

Medicinal Research Reviews

120

100

View full text Add to dashboard Cite

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“…DMF is rapidly metabolized in the plasma of patients to monomethyl-fumarate (MMF) and has a C max in plasma of ∼15 µM, with an approximate steady state tissue and plasma concentration of 5 µM. Most laboratory-based oncology studies have used DMF, not MMF, and in over 90% of all publications have used the drug above the clinically relevant range, and the range recommended by the drug makers, Biogen (15,16). Thus, very little is known about the "real" biology of MMF.…”

Section: Introductionmentioning

confidence: 99%

Fingolimod Augments Monomethylfumarate Killing of GBM Cells

et al. 2020

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Previously we demonstrated that the multiple sclerosis drug dimethyl fumarate (DMF) and its plasma breakdown product MMF could interact with chemotherapeutic agents to kill both GBM cells and activated microglia. The trial NCT02337426 demonstrated the safety of DMF in newly diagnosed GBM patients when combined with the standard of care Stupp protocol. We hypothesized that another multiple sclerosis drug, fingolimod (FTY720) would synergize with MMF to kill GBM cells. MMF and fingolimod interacted in a greater than additive fashion to kill PDX GBM isolates. MMF and fingolimod radiosensitized glioma cells and enhanced the lethality of temozolomide. Exposure to [MMF + fingolimod] activated an ATM-dependent toxic autophagy pathway, enhanced protective endoplasmic reticulum stress signaling, and inactivated protective PI3K, STAT, and YAP function. The drug combination reduced the expression of protective c-FLIP-s, MCL-1, BCL-XL, and in parallel caused cell-surface clustering of the death receptor CD95. Knock down of CD95 or over-expression of c-FLIP-s or BCL-XL suppressed killing. Fingolimod and MMF interacted in a greater than additive fashion to rapidly enhance reactive oxygen species production and over-expression of either thioredoxin or super-oxide dismutase two significantly reduced the drug-induced phosphorylation of ATM, autophagosome formation and [MMF + fingolimod] lethality. In contrast, the production of ROS was only marginally reduced in cells lacking ATM, CD95, or Beclin1. Collectively, our data demonstrate that the primary generation of ROS by [MMF + fingolimod] plays a key role, via the induction of toxic autophagy and death receptor signaling, in the killing of GBM cells.

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“…Target concentrations of MMF were reported to be in the range of 10–30 μM, with 15 μM being tested most commonly although 5 μM was used occasionally [1;3;49;58]. For microdialysis drug application we used 1 mM because a 100 fold higher concertation is needed inside the probe due to the concentration gradient across the microdialysis membrane as indicated by our own work comparing drug effects in brain slices with microdialysis drug application for a variety of compounds [12;31;36;46].…”

Section: Discussionmentioning

confidence: 99%

“…Concentrations for microdialysis administration were based on the literature that reported target concentrations of MMF in the range of 10–30 μM, with 15 μM being the most commonly tested concentration although 5 μM was used occasionally [1;3;49;58]. Due to the concentration gradient across the microdialysis membrane a 100 fold higher concertation is needed inside the probe [12;31;36;46], and so we used 1 mM.…”

Section: Methodsmentioning

confidence: 99%

Monomethyl fumarate inhibits pain behaviors and amygdala activity in a rat arthritis model

Kim

Thompson

et al. 2017

PAIN

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Neuroplasticity in the amygdala, a brain center for emotions, leads to increased neuronal activity and output that can generate emotional-affective behaviors and modulate nocifensive responses. Mechanisms of increased activity in the amygdala output region (central nucleus, CeA) include increased reactive oxygen species, and so we explored beneficial effects of monomethyl fumarate (MMF), which can have neuroprotective effects through the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) anti-oxidant response pathway. Systemic (intraperitoneal) MMF dose-dependently inhibited vocalizations and mechano-sensitivity (hindlimb withdrawal reflexes) of rats in an arthritis pain model (kaolin/carrageenan-induced mono-arthritis in the knee). Stereotaxic administration of MMF into the CeA by microdialysis also inhibited vocalizations but had a limited effect on mechano-sensitivity, suggesting a differential contribution to emotional-affective versus sensory pain aspects. Extracellular single-unit recordings of CeA neurons in anesthetized rats showed that stereotaxic administration of MMF into the CeA by microdialysis inhibited background activity and responses of CeA neurons to knee joint stimulation in the arthritis pain model. MMF had no effect on behaviors and neuronal activity under normal conditions. The results suggest that MMF can inhibit emotional-affective responses in an arthritis pain model through an action that involves the amygdala (CeA).

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Regulation of dimethyl-fumarate toxicity by proteasome inhibitors

Cited by 26 publications

References 46 publications

Dimethyl fumarate, a two‐edged drug: Current status and future directions

Dimethyl fumarate, a two‐edged drug: Current status and future directions

Fingolimod Augments Monomethylfumarate Killing of GBM Cells

Monomethyl fumarate inhibits pain behaviors and amygdala activity in a rat arthritis model

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