Dimethylfumarate Impairs Melanoma Growth and Metastasis

Loewe, Robert; Valero, Teresa; Kremling, Silvia; Pratscher, Barbara; Kunstfeld, Rainer; Pehamberger, Hubert; Petzelbauer, Peter

doi:10.1158/0008-5472.can-06-2397

Cited by 99 publications

(122 citation statements)

References 42 publications

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“…14 In addition, DMF switched the immune system towards a Th2 anti-inflammatory type response through the activation of type II DCs and the suppression of type I DCs, which consequently inhibits the generation of inflammatory Th1 or Th17 cells. 17 It has been reported that DMF inhibits the proliferation of melanoma cells 18 and synergizes with dacarbazine to influence the migration of tumor cells. 25 Whether DMF or the DMF derivative MMF exerts any effect on NK cells remains unknown.…”

Section: Discussionmentioning

confidence: 99%

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Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

et al. 2014

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Dimethyl fumarate (DMF) is a new drug used to treat multiple sclerosis (MS) patients. Here, we examined the effects of DMF and the DMF metabolite monomethyl fumarate (MMF) on various activities of natural killer (NK) cells. We demonstrated that MMF augments the primary CD56 1 , but not CD56 2 , NK cell lysis of K562 and RAJI tumor cells. MMF induced NKp46 expression on the surface of CD56 1 , but not CD56 2 , NK cells after incubation for 24 h. This effect was closely correlated with the upregulation of CD107a expression on the surface of CD56 1 NK cells and the induction of Granzyme B release from these cells through this metabolite. An anti-NKp46 antibody inhibited the MMF-induced upregulation of CD107a and the lysis of tumor cells through CD56 1 NK cells. Thus, these results are the first to show that MMF augments CD56 1 NK cell lysis of tumor target cells, an effect mediated through NKp46. This novel effect suggests the use of MMF for therapeutic and/or preventive protocols in cancer.

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Section: Discussionmentioning

confidence: 99%

“…Interestingly, DMF might have anti-tumor effects. In an experimental model of melanoma, Loewe et al 18 observed that DMF reduces metastases in SCID mice and inhibits the in vitro proliferation of the human melanoma cells A375 and M24met. However, the DMF metabolite monomethyl fumarate (MMF) has not been studied in detail.…”

Section: Introductionmentioning

confidence: 99%

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

et al. 2014

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“…[22][23][24] DMF has almost no apoptotic effect on resting T cells or other bystander cells, which correlates with the fact that they do not show elevated NF-kB activity. 21 Consequently, marked clinically apparent immunosuppression usually does not result from DMF treatment, despite its pleiotropic cellular effects.…”

Section: Introductionmentioning

confidence: 94%

Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB

Nicolay

Müller‐Decker

Schroeder

et al. 2016

Blood

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Key Points• DMF induces specific cell death in CTCL cells and inhibits CTCL tumor growth and metastasis in vivo via inhibition of NF-kB.• DMF therefore represents a promising, nontoxic novel therapeutic approach to treating CTCL.Despite intensive efforts in recent years, a curative therapy for cutaneous T-cell lymphoma (CTCL) has not yet been developed. Therefore, the establishment of new therapeutic approaches with higher efficacy rates and milder side effects is strongly desired. A characteristic feature of the malignant T-cell population in CTCL is resistance toward cell death resulting from constitutive NF-kB activation. Therefore, NF-kBdependent cell death resistance represents an interesting therapeutic target in CTCL because an NF-kB-directed therapy would leave bystander T cells widely unaffected. We investigated the effects of dimethyl fumarate (DMF) on CTCL cells in vitro and in vivo. DMF induced cell death in primary patient-derived CD4 1 cells and CTCL cell lines, but hardly in T cells from healthy donors. DMF-induced cell death was linked specifically to NF-kB inhibition. To study the impact of DMF in vivo, we developed 2 CTCL xenograft mouse models with different cutaneous localizations of the T-cell infiltrate. DMF treatment delayed the growth of CTCL tumors and prevented formation of distant metastases. In addition, DMF induced increased cell death in primary CTCL tumors and in liver metastases. In summary, DMF treatment represents a remarkable therapeutic option in CTCL because it restores CTCL apoptosis in vitro and in preclinical models in vivo and prevents spreading of the disease to distant sites. DMF treatment is of particular promise in CTCL because DMF is already in successful clinical use in the treatment of psoriasis and multiple sclerosis allowing fast translation into clinical studies in CTCL. (Blood. 2016;128(6):805-815)

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“…As positive controls, native and mock-transfected A375-SM cells were driven to apoptosis by TNF alpha exposition (recombinant TNF alpha, end concentration 25 ng/ml, Strathmann Biotech, Hamburg, Germany) as described elsewhere. 31 After 8 hr, cells were washed, harvested in 1 ml fresh FCS-free medium and split up to ten 96 wells per sample. Apoptosis was assayed using the Caspase-Glo TM 3/7 Reagent (Promega, Madison, WI, USA) according to the manufacturer's recommendations.…”

Section: Apoptosis Assaymentioning

confidence: 99%

RBP2‐H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells

Roesch

Mueller²,

Stempfl

et al. 2007

Intl Journal of Cancer

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The RBP2-H1/JARID1B nuclear protein belongs to the ARID family of DNA-binding proteins and is a potential tumor suppressor that is lost during melanoma development. As we have recently shown, one physiological function of RBP2-H1/JARID1B is to exert cell cycle control via maintenance of active retinoblastoma protein. We now add new evidence that RBP2-H1/JARID1B can also directly regulate gene transcription in a reporter assay system, either alone or as part of a multimolecular complex together with the developmental transcription factors FOXG1b and PAX9. In melanoma cells, chromatin immunoprecipitation combined with promoter chip analysis (ChIP-on-chip) suggests a direct binding of re-expressed RBP2-H1/JARID1B to a multitude of human regulatory chromosomal elements (promoters, enhancers and introns). Among those, a set of 23 genes, including the melanoma relevant genes CDK6 and JAG-1 could be confirmed by cDNA microarray analyses to be differentially expressed after RBP2-H1/JARID1B re-expression. In contrast, in nonmelanoma HEK 293 cells, RBP2-H1/JARID1B overexpression only evokes a minor transcriptional response in cDNA microarray analyses. Because the transcriptional regulation in melanoma cells is accompanied by an inhibition of proliferation, an increase in caspase activity and a partial cell cycle arrest in G1/0, our data support an anti-tumorigenic role of RBP2-H1/JARID1B in melanocytic cells. ' 2007 Wiley-Liss, Inc.Key words: melanoma; transcription; gene expression; retinoblastoma protein binding protein; apoptosisIn 1999, our group detected a gene transcript suppressed by UV-B in normal human melanocytes (Acc. No. AF087481, 1 ). Based on its homology to the previously described RBP2, 2 this new gene was termed retinoblastoma binding protein 2-homolog 1 (RBP2-H1). Subsequent expression studies revealed a frequent loss of RBP2-H1 in the majority of advanced and metastatic melanomas in vivo and in many melanoma cell lines, whereas benign melanocytic tumors, normal tissues and other cancer types mostly retain RBP2-H1. 1,3 Recently, we showed that RBP2-H1 has a tumor suppressive activity partly due to binding and stabilization of hypophosphorylated retinoblastoma protein (pRb) leading to maintenance of pRb-mediated cell cycle control. 4 As a result of truncation studies, we located the pRb-binding activity of RBP2-H1 to its C-term, containing a homolog region of the non-T/E1A-pRb binding domain known from other retinoblastoma binding proteins like RBP2. 5 Moreover, RBP2-H1 and its splicing variants PLU-1 and RBBP2H1a contain further well-conserved domains known to be involved in direct gene regulation and chromatin homeostasis, e.g. 3 PHD motifs and the ARID (AT-rich interacting) DNA-binding domain. [6][7][8][9] Although the 3 splicing variants show a cDNA sequence homology of more than 98%, RBP2-H1 differs from PLU-1 and RBBP2H1a by an additional exon encoding a region with strong homology to chromosomal ALU repeats. Thus, previously reported differences in tissue expression (PLU-1 shows a restricted expre...

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Dimethylfumarate Impairs Melanoma Growth and Metastasis

Cited by 99 publications

References 42 publications

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB

RBP2‐H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells

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