Role of Dimethyl Fumarate in the Treatment of Glioblastoma Multiforme

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Iranian Journal Review Article of Neurology Iran J Neurol 2019; 18(3): 127-33

Role of dimethyl fumarate in the

Received: 11 Mar. 2019 treatment of glioblastoma Accepted: 16 May 2019 multiforme: A review article

Reza Ahmadi-Beni1, Ali Najafi2,3, Seyed Mehrdad Savar4, Niayesh Mohebbi5, Alireza Khoshnevisan6

1 Department of Medical Genetics, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran 2 Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 3 Student Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran 4 School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran 5 Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran 6 Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

Keywords therapeutic effects on GBM. Brain Neoplasms; Glioblastoma; Fumarates; Dimethyl Fumarate; Neuroprotective Agents; Drug Repurposing Introduction Glioblastoma multiforme (GBM) establishes more

than half of the malignant gliomas, the most

malignant and aggressive primary brain tumor, Abstract and is mainly a malignancy of older ages.1,2 It is Glioblastoma multiforme (GBM), the most frequent malignant and aggressive primary brain tumor, is characterized by genetically unstable characterized by genetically unstable heterogeneous heterogeneous cells, diffused growth pattern, cells, diffused growth pattern, microvascular microvascular proliferation, and resistance to 3,4 proliferation, and resistance to chemotherapy. chemotherapy. Current therapy includes Extensive investigations are being carried out to maximal surgical resection followed by identify the molecular origin of resistance to chemo- chemoradiotherapy, but only less than 5% of and radio-therapy in GBM and find novel targets for patients with GBM survive 5 years postdiagnosis therapy to improve overall survival rate. Dimethyl and the median survival is about 15 months.2,5 fumarate (DMF) has been shown to be a safe drug with limited short and long-term side effects, and fumaric acid esters (FAEs), including DMF, present both anti-

oxidative and anti-inflammatory activity in different How to cite this article: Ahmadi-Beni R, Najafi A, cell types and tissues. DMF has also anti-tumoral and Savar SM, Mohebbi N, Khoshnevisan A. Role of neuroprotective effects and so it could be repurposed dimethyl fumarate in the treatment of glioblastoma in the treatment of this invasive tumor in the future. multiforme: A review article. Iran J Neurol 2019; 18(3): Here, we have reviewed DMF pharmacokinetics and 127-33. different mechanisms by which DMF could have

Intensive investigations are being carried out to help of ubiquitously-found esterases in GI tract, identify the molecular origin of resistance to tissues, and blood.18,19 The resulting active chemo- and radio-therapy in GBM, looking into metabolite is monomethyl fumarate (MMF). This novel therapeutic targets and also new drugs that conversion takes place very fast and as a result, may improve overall survival rate.6-8 DMF is not detectable in plasma. So, all related Dimethyl fumarate (DMF) is an anti- pharmacokinetic information is gathered from inflammatory and safe medication that has been MMF which is a negatively-charged molecule. used for many years in the treatment of MMF cannot cross cell membrane, but it is a psoriasis.9,10 Studies reveal that the beneficial hydroxycarboxylic acid receptor 2 (HCA2) agonist effects of this fumaric acid ester (FAE) arise from and may exert its effects through a HCA2- its potency to reduce the T cell-mediated mediated manner.20 Also, MMF has some HCA2- inflammatory gene expression, including independent effects like activating the pathway of inflammatory cytokines and chemokines. nuclear-factor (erythroid-derived 2)-related factor- DMF is a drug with an acceptable safety and its 2 (Nrf2).21,22 short and long-term side effects are few [most Following oral administration of Tecfidera, a commonly consisting of flushing, gastrointestinal median time of 2 to 2.5 hours is needed to peak 11-13 (GI) complaints, and leukocytopenia]. plasma concentration (Tmax). In case of Tecfidera, Regarding its good safety profile, a formulation of the peak plasma concentration (Cmax) is decreased DMF called BG-12 was developed for the treatment with high-fat high-calorie meal by 40% and the 13,14 of multiple sclerosis (MS), and then proposed to Tmax is delayed from 2.0 hours to 5.5 hours. During be repurposed for GBM treatment.15 Recently fed state, the flushing occurrence could be different mechanisms for the role of DMF in diminished by about 25%.19,23 neuroprotection and tumor cell destruction have MMF is further metabolized through the citric been demonstrated (Figure 1). Here, we review acid cycle (Krebs cycle). MMF, together with fumaric, some papers that have been published by authors glucose, and citric acid are of the most metabolites in investigating mechanisms that could be beneficial plasma. The primary path of removal is by exhalation in the treatment of GBM by DMF, but first we of carbon dioxide (CO2) that accounts for about 60% discuss a little about the pharmacokinetics of DMF. of Tecfidera dose, and the other routes include renal and fecal elimination.23

NO, TNF α, IL1β, IL6, MCP-1/CCL2 Keap1-Nrf2-ARE Tumor heterogeneity poses one of the most important obstacles in the definitive diagnosis and targeted treatment of GBM, making differences DMF happen in treatment response and outcome. Understanding and deciphering tumor heterogeneity can bring forth a new patient- tailored treatment regimen.24,25 In addition to

NF κΒ Nrf2 intertumoral heterogeneity which refers to the difference in mutation profiles between patients

Figure 1. Four main molecular pathways which make with the same tumor type, allowing molecular dimethyl fumarate (DMF) a suitable anti-cancer drug for subtype classification, there is also intratumoral glioblastoma multiforme (GBM) therapy heterogeneity referring to the difference in genetic alterations between cancer cells within a tumor.24,26 Intratumoral heterogeneity changes during usage DMF is available as a delayed-release capsule of therapy which presents challenges in the setting under the trade name of Tecfidera which is of GBM recurrence, as recurrent tumor cells approved by Food and Drug Administration usually exhibit resistance to the traditional (FDA) to be used for relapsing remitting MS treatment options and express different mutations (RRMS) therapy.16 DMF can easily enter cells as it in comparison with the original tumor.24,27 This is a highly lipophilic substance.17 However, once intratumoral heterogeneity has wide significance DMF releases from its capsule (as a drug), it for the clinical practice outcome of patients, undergoes rapid pre-systemic hydrolysis with the particularly in the current personalized medicine

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perspective according to analysis of genomic endothelial cells reduces expression of vascular material of an individual cancer biopsy.28 endothelial growth factor receptor-2 (VEGFR-2), Glutathione S-transferases (GSTs) [GSTs are inhibits migration of endothelial cells, and stimulates detoxification agents that are used as catalyzers to endothelial cell apoptosis, which may elucidate why conjugate the reduced form of glutathione (GSH) DMF may be valuable in proliferative diseases to xenobiotic substrates] which are induced by including psoriasis, rheumatoid arthritis (RA), tumor DMF, were investigated in psoriasis and it has growth, and metastasis.40,41 been observed that Val/Val GSTP1 polymorphism There are a few studies investigating the effects is associated with non-responsiveness to treatment of DMF in gliomas which have shown that with this FAEs.17 This polymorphism has also been cytotoxicity of other antitumor agents is increased suggested as a potential biomarker predicting the by pretreatment with DMF.38 Ghods et al.42 in a status of responsiveness to DMF in other study analyzed the potential antitumor properties diseases.17 There is no information about the of DMF in several glioma models by evaluating its impact of GBM heterogeneity on response to DMF effects on proliferation, cell lysis, and therapy and comprehensive studies on this field differentiation. Human glioblastoma A172, mouse are required. glioma Gl261, and patients’ glioblastoma cells were exposed to DMF at therapeutic (100 μm) and supra-therapeutic concentrations (300 μm) for In addition to its effects on the adaptive immune evaluation of proliferation, cellular death, and response, DMF also represses the inherent differentiation. The lactate dehydrogenase (LDH) inflammatory responses of glial cells via cell lysis assay and 5-bromo-2’-deoxyuridine decreasing the nuclear factor kappa B (NF-κΒ) (BrdU) proliferation assay were also used. signaling pathways activation.29,30 The DMF action Differentiation was evaluated by is conducted through suppression of signals which immunocytochemistry (ICC). In the study, are transmitted by the Rel proteins, and also by proliferation considerably decreased and tumor suppressing the complex of inhibitor of κΒ (IκΒ) cell death significantly increased in all tumor cell kinase (IKK) and translocation of lines after exposure to DMF. A significant decrease NF-κΒ to the nucleus, that results in halting gene in CD133 expression was observed in addition to a transcription. NF-κΒ complexes are normally decline in the expression of NF-κΒ after exposure situated inside the cell cytoplasm by the inhibitory to DMF. Also, a drastic impact of DMF on IκΒ complex. Inflammatory mediators cause decreasing the formation of both neurospheres and phosphorylation of IκΒ complex through IKK the expression of CD133 cells in human action, resulting in ubiquitin-mediated glioblastoma cells was demonstrated. Results degradation of IκΒ. This allows the NF-κΒ to revealed that DMF might suppress tumor translocate into the nucleus and subsequently proliferation by diminishing these CD133-marked leads to the downstream transcription activation.31 glioblastoma stem cells (GSCs) in the tumor.42 DMF decreases inflammatory mediators such as These findings warrant further studies on the DMF tumor necrosis factor-α effects on several hallmarks of GSCs in more detail as (TNF-α), interleukin-1β (IL-1β), nitric oxide (NO), new approaches to isolate and characterize tumoral and IL-6, and via suppression of NF-κΒ, it can cells that satisfy the functional characteristics of GSCs induce apoptosis in several types of cell like T continue to be explored.43,44 cells.32 DMF has been shown to limit the in vitro In another study in four glioblastoma cell lines, and in vivo growth of melanoma.33 Correlation of cytotoxicity of the bioreductive antitumor agents, NF-κΒ activity with angiogenesis, cell mitomycin C (MMC) and streptonigrin (SN), in proliferation, and anti-apoptosis in different solid presence or absence of DMF as inducer of DT- tumors has been demonstrated by previous diaphorase (DTD) (i.e., an obligate two-electron studies.31,34,35 The ability to suppress Rel protein reductase that bioactivates chemotherapeutic pathway reduces NF-κΒ nuclear translocation, and quinines) was compared with the 1,3-bis(2- transcription inhibition of inflammatory cytokines chloroethyl)-1-nitrosourea (BCNU) as a usual is possible antitumor mechanism of DMF.36,37 chemotherapeutic agent. A significant increase in Inhibiting angiogenesis via suppressing NF-κΒ in the cytotoxicity of SN and MMC was observed in endothelial cells may also halt tumor glioblastoma cell lines when using DMF in the progression.38,39 Suppression of NF-κΒ in pretreatment stage, but there was no effect on the

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BCNU cytotoxicity. In three, out of four, studied including that they are entirely in vitro glioblastoma cell lines, spectrophotometric investigations. As a result, in vivo evaluation of measurements showed that DMF drastically DMF effects on GBM is needed to be carried out.42 increased cytochrome b5 reductase (CYB5R) and DTD activity and reduced GST.45 When DTD inhibitor, dicumarol, is added, it considerably DMF due to its neuroprotective role might support suppresses cytotoxic effects of SN and MMC, and neuronal survival after operation in brain tumors also reverses the increased cytotoxicity of either including GBM. One of the examples of combination of DMF with SN or MMC in the neuroprotective properties of DMF is in ischemia. studied glioblastoma-derived cell lines. DMF protects the BBB integrity and so attenuates Combination of CYB5R and DTD inducers with cerebral edema formation. At a first glance, bioreductive antitumor agents could be a improved vascular permeability seems to assist promising strategy for the treatment of GBM. access of erythropoietin (EPO) and some other MMC does not penetrate an intact blood-brain neuroprotective factors to the brain parenchyma barrier (BBB) and so, is not known to be an active and looks to be favorable for neuronal survival. agent against glioblastoma. SN can traverse the BBB, Nevertheless, edemogenesis causes elevated but because of its myelotoxicity cannot be used intracranial pressure (ICP) and unfavorable effects clinically without limitation. Temozolomide is a on oxygen distribution, and consequently the clinically-developed alkylating agent. This prodrug initial neuroprotective impact would be abolished. is the analog of imidazotetrazine that in solution FAEs [methyl hydrogen fumarate (MHF) and spontaneously produces a triazine derivative [5-(3- DMF] have anti-oxidative and anti-inflammatory methyltriazen-1-yl)-imidazole-4-carboxamide activities in different tissues and cell types such as (MTIC)]. It goes across BBB with concentrations in neurons and astrocytes confronted to oxidative the central nervous system (CNS) near 30% of stress situations. Moreover, preconditioning with plasma concentrations.46 Then, it renders DMF diminishes the formation of the monomethylation of deoxyribonucleic acid (DNA) proinflammatory mediators including IL-6, IL-1β, purine bases (N3-adenine, O6-guanine, N7- NO, and TNF-α in lipopolysaccharide (LPS)- guanine).47 MMF enhances the toxicity of activated astrocytes and microglia.50 Also, MMF temozolomide and ionizing radiation.15 Another puts freshly isolated activated microglia to death drug that has been experimentally used is and reduces TNF-α, IL-6, and TGF-β production,15 bevacizumab (Avastin). Bevacizumab directly and the last one prevents TGF-β-induced ZEB1- binds to vascular endothelial growth factor A dependent mesenchymal transdifferentiation in (VEGFA) to inhibit its angiogenicity. Inherent and GBM that causes tumor invasion.51 In an in vivo acquired resistance to temozolomide and study, an acute ischemic stroke model for BBB bevacizumab, in addition to different side effects, breakdown and cerebral edema formation was presents major obstacles to successful treatment.26 used. DMF systemic pre-treatment decreased Nevertheless, for avoiding these obstacles, formation of edema throughout ischemic stroke concomitant use of DMF with SN, temozolomide and reduced the activity of brain tissue matrix or bevacizumab, or a combination of them metalloproteinases (MMPs) upon ischemic warrants further study, that may also permit stroke.52 It also prevented the disruption of inter- administration of lower doses of the endothelial tight junctions (TJs) during ischemic chemotherapeutic agents which will decrease stroke by triggering the antioxidant nuclear-factor systemic toxicity.38 The only phase I clinical trial Nrf2 pathway. Findings denoted that neuronal using DMF in patients with GBM showed that it apoptosis, elicited by ischemic stroke, was might be safely used in combination with radiation diminished by systemically-applied DMF.52 DMF, and temozolomide.48 Also, recently, research is on by motivating the redox-sensitive transcription the way for enhancing DMF bioavailability and factor Nrf2, impedes inflammatory cytokines and delivery to improve its concentrations in the so, decreases migration of leukocytes. In fact, brain.49 increased Nrf2 activity is the cause of protection of These findings suggest that DMF may be the BBB. Proinflammatory factors such as considered for further antitumor investigations monocyte chemoattractant protein-1 (MCP- and it presents a new treatment approach for brain 1/CCL2) and TNF-α in astrocytes and endothelial tumors. These studies have some limitations cells exposed to ischemic condition are abolished

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by DMF. DMF and its primary metabolite, MMF, in chronic experimental autoimmune improve the in vitro survival of neurons exposed encephalomyelitis (EAE). Both DMF and MHF to oxidative stresses including hydrogen peroxide have a noteworthy beneficial influence on the 21,52 (H2O2) and glutamate toxicity. Besides, it has disease course, and histology shows a significantly been shown that FAEs do not activate the pathway decreased macrophage inflammation in the spinal of hypoxia-inducible factor (HIF); so, it seems that cord.60 the pathway does not participate to FAE-mediated neuroprotection significantly.53,54 In recent years, studies revealed that systemic Generally, DMF is a safe drug with acceptable DMF therapy successfully improved neurological tolerability profile and its short and long-term recovery, decreased brain edema, and improved side effects are few.13,23 Nevertheless, DMF may resolution of hematoma in rodent models of acute cause flushing, rash, lymphocytopenia, albumin intracerebral hemorrhage (ICH).53,55 These and urine presence, erythema, and GI events such as some other evidence support the idea that DMF nausea, abdominal pain, vomiting, dyspepsia, helps neuronal survival in apoptotic processes and and diarrhea, but the occurrence of adverse slowly-progressing diseases.21,52,56 effects are not usually much higher than placebo- The inflammatory response and oxidative treated control groups.13,19,61 The occurrence of GI stress can cause brain damage in subarachnoid events in the early course of treatment (primarily hemorrhage (SAH) and DMF also significantly in first month) is higher and commonly ameliorates the early brain damage and learning diminishes through the time in DMF-treated deficiencies in animal models of SAH.57 This patients, in comparison to placebo.62,63 The neuroprotective effect is implemented through serious GI events incidence was 1% in activation of the Kelch-like ECH-associated DMF-treated patients.23 It is suggested from a protein 1–Nrf2–antioxidant-response element phase IV clinical trial that GI events seen due to (Keap1-Nrf2-ARE) system, which causes the DMF could be well managed with common downregulation of oxidative stress and symptomatic therapy.64 inflammation. In one study, SAH model in rats was achieved by 300 μl autologous blood injection into their chiasmatic cistern. In the group treated by Glioblastoma is a highly-malignant and difficult DMF, after the onset of SAH, rats were given 15 to treat brain tumor, and despite many mg/kg DMF through oral gavage twice daily for 2 investigations on its therapy, only a few drugs days. Brain edema, BBB damage, cortical with little success have been used clinically for its apoptosis, necrosis of the neurons, learning management. Although development of novel deficiencies, and alterations in the Keap1-Nrf2- drugs is a matter of importance, finding eligible ARE pathway were studied. Treatment with DMF drugs is a matter of time and budget. Considering after SAH, significantly upregulated the Keap1- these difficulties, repurposing FDA-approved Nrf2-ARE signaling-related genes expressions.57 drugs might be a remedial shortcut in comparison Furthermore, antioxidant activity of DMF is with newly-developed ones. DMF, as an FDA- also applied through binding of Nrf2 to promoter- approved drug, is ready for clinical research to be located AREs of protection genes including considered as a therapeutic and adjuvant option nicotinamide adenine dinucleotide phosphate for GBM therapy. DMF is a FAE which regarding (NADPH)-quinone-oxidoreductase-1 (NQO-1)37 its anti-tumoral and neuroprotective effects in and heme oxygenase-1 (HO-1). It finally increases GBM, more studies are necessary to clear its the intracellular levels of antioxidant GSH.11,56,58 molecular functions especially for suppressing FAE treatment leads to upregulation of the NF-κΒ and triggering Nrf2. Finally, like GBM detoxification enzyme NQO-1 and reduction of the heterogeneity, other challenges of GBM therapy, neurotoxic agent NO. DMF also upregulates HO-1, like bypassing BBB, deserve equal attention to as an anti-stress protein in the human peripheral achieve effective drug concentrations in the blood mononuclear cells (PBMCs). DMF has an tumor tissue for fully effective utilization of DMF important inhibitory influence on LPS-activated in GBM eradication setting. NO burst in microglia and causes apoptosis in PBMCs.59,60 It is reported that FAEs show protective effects The authors declare no conflict of interest in

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this study. None.

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