Therapeutic Potential of Fingolimod and Dimethyl Fumarate in Non-Small Cell Lung Cancer Preclinical Models

Rupp, Tristan; Debasly, Solène; Genest, Laurie; Froget, Guillaume; Castagné, Vincent

doi:10.3390/ijms23158192

Cited by 5 publications

(12 citation statements)

References 89 publications

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“…DMF is a drug currently used for the treatment of psoriasis and multiple sclerosis [ 30 ]; an ongoing clinical trial was recently designed to test DMF in cutaneous T-cell lymphoma [ 41 , 56 ], suggesting its potential use in lymphoid malignancies. Similarly, several preclinical studies proposed the use of DMF in different types of leukemia and solid tumors: DMF was active in AML differentiation therapy [ 57 ], inhibited melanoma growth and metastasis [ 58 – 60 ], blocked constitutive NF-kB signaling in breast cancer cells resulting in apoptosis [ 61 , 62 ], and repressed tumor progression in non-small cell lung cancer models [ 63 ]. However, our study is the first to focus on DMF-induced cell death in CLL where it may target a novel vulnerability in the disease towards an actual clinical translation.…”

Section: Discussionmentioning

confidence: 99%

Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death

Mantione,

Meloni,

Sana

et al. 2024

Cell Death Dis

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Microenvironmental signals strongly influence chronic lymphocytic leukemia (CLL) cells through the activation of distinct membrane receptors, such as B-cell receptors, and inflammatory receptors, such as Toll-like receptors (TLRs). Inflammatory pathways downstream of these receptors lead to NF-κB activation, thus protecting leukemic cells from apoptosis. Dimethyl fumarate (DMF) is an anti-inflammatory and immunoregulatory drug used to treat patients with multiple sclerosis and psoriasis in which it blocks aberrant NF-κB pathways and impacts the NRF2 antioxidant circuit. Our in vitro analysis demonstrated that increasing concentrations of DMF reduce ATP levels and lead to the apoptosis of CLL cells, including cell lines, splenocytes from Eµ-TCL1-transgenic mice, and primary leukemic cells isolated from the peripheral blood of patients. DMF showed a synergistic effect in association with BTK inhibitors in CLL cells. DMF reduced glutathione levels and activated the NRF2 pathway; gene expression analysis suggested that DMF downregulated pathways related to NFKB and inflammation. In primary leukemic cells, DMF disrupted the TLR signaling pathways induced by CpG by reducing the mRNA expression of NFKBIZ, IL6, IL10 and TNFα. Our data suggest that DMF targets a vulnerability of CLL cells linked to their inflammatory pathways, without impacting healthy donor peripheral blood mononuclear cells.

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Section: Discussionmentioning

confidence: 99%

Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death

Mantione,

Meloni,

Sana

et al. 2024

Cell Death Dis

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“…TMZ was used at 0.01, 0.1, 1, 10, 50, 100, 250, 500, and 1000 µM [ 45 ] and was diluted in culture medium containing up to 0.5% dimethylsulfoxide (DMSO, reference D8418, Merck ® , Rahway, NJ, USA). Fingolimod was used at 0.1, 0.5, 1, 2.5, 5, and 10 µM [ 29 , 33 ] and was diluted in culture medium; above these doses Fingolimod was not fully soluble.…”

Section: Methodsmentioning

confidence: 99%

“…Housing was adapted according to previous work [ 29 ]. Female C57BL/6JRj or BALB/cAnN-Foxn1nu/nu/Rj (=BALB/c-nude) mice were supplied by Janvier Labs.…”

Section: Methodsmentioning

confidence: 99%

“…Fingolimod retains T cells in secondary lymph organs through the inhibition of S1PRs, including S1PR1, S1PR3, S1PR4, and S1PR5 [ 24 , 25 ], limiting T cell brain infiltration and lowering disease progression [ 26 ]. Interestingly, preclinical studies suggest that Fingolimod may favor an anti-tumoral response for different types of cancer, such as triple-negative breast cancer and lung cancer [ 25 , 27 , 28 , 29 , 30 ]. Fingolimod can cross the blood–brain barrier as radiolabeled fingolimod accumulates in the white matter of the central nervous system (CNS) [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models

Davy,

Genest,

Legrand

et al. 2023

Cancers

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Glioblastomas are malignant brain tumors which remain lethal due to their aggressive and invasive nature. The standard treatment combines surgical resection, radiotherapy, and chemotherapy using Temozolomide, albeit with a minor impact on patient prognosis (15 months median survival). New therapies evaluated in preclinical translational models are therefore still required to improve patient survival and quality of life. In this preclinical study, we evaluated the effect of Temozolomide in different models of glioblastoma. We also aimed to investigate the efficacy of Fingolimod, an immunomodulatory drug for multiple sclerosis also described as an inhibitor of the sphingosine-1-phosphate (S1P)/S1P receptor axis. The effects of Fingolimod and Temozolomide were analyzed with in vitro 2D and 3D cellular assay and in vivo models using mouse and human glioblastoma cells implanted in immunocompetent or immunodeficient mice, respectively. We demonstrated both in in vitro and in vivo models that Temozolomide has a varied effect depending on the tumor type (i.e., U87MG, U118MG, U138MG, and GL261), demonstrating sensitivity, acquired resistance, and purely resistant tumor phenotypes, as observed in patients. Conversely, Fingolimod only reduced in vitro 2D tumor cell growth and increased cytotoxicity. Indeed, Fingolimod had little or no effect on 3D spheroid cytotoxicity and was devoid of effect on in vivo tumor progression in Temozolomide-sensitive models. These results suggest that the efficacy of Fingolimod is dependent on the glioblastoma tumor microenvironment. Globally, our data suggest that the response to Temozolomide varies depending on the cancer model, consistent with its clinical activity, whereas the potential activity of Fingolimod may merit further evaluation.

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“…Specifically, this molecule can induce cell death in different types of blood cancers [ 81 , 82 , 83 ]. Similarly, in vitro and in vivo pre-clinical studies demonstrated that in solid tumors DMF exerts a therapeutic potential both alone and in combination with other compounds [ 26 , 84 , 85 , 86 , 87 ].…”

Section: Current Clinical Applications and Clinical Trialsmentioning

confidence: 99%

The Challenge of Dimethyl Fumarate Repurposing in Eye Pathologies

Manai

Govoni

Amadio

2022

Cells

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Dimethyl fumarate (DMF) is a small molecule currently approved and used in the treatment of psoriasis and multiple sclerosis due to its immuno-modulatory, anti-inflammatory, and antioxidant properties. As an Nrf2 activator through Keap1 protein inhibition, DMF unveils a potential therapeutical use that is much broader than expected so far. In this comprehensive review we discuss the state-of-art and future perspectives regarding the potential repositioning of this molecule in the panorama of eye pathologies, including Age-related Macular Degeneration (AMD). The DMF’s mechanism of action, an extensive analysis of the in vitro and in vivo evidence of its beneficial effects, together with a search of the current clinical trials, are here reported. Altogether, this evidence gives an overview of the new potential applications of this molecule in the context of ophthalmological diseases characterized by inflammation and oxidative stress, with a special focus on AMD, for which our gene–disease (KEAP1-AMD) database search, followed by a protein–protein interaction analysis, further supports the rationale of DMF use. The necessity to find a topical route of DMF administration to the eye is also discussed. In conclusion, the challenge of DMF repurposing in eye pathologies is feasible and worth scientific attention and well-focused research efforts.

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Therapeutic Potential of Fingolimod and Dimethyl Fumarate in Non-Small Cell Lung Cancer Preclinical Models

Cited by 5 publications

References 89 publications

Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death

Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death

Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models

The Challenge of Dimethyl Fumarate Repurposing in Eye Pathologies

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