Dimethyl Fumarate Induces Apoptosis<i>via</i>Inhibiting NF-κB and STAT3 Signaling in Adult T-cell Leukemia/Lymphoma Cells

Maeta, Takahiro; Sato, Takahiro; Asano, Keisuke; Ito, Shigeki

doi:10.21873/anticanres.15709

Cited by 11 publications

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“…DMF suppresses phosphorylation of CARD11 and IKKα/β, and expression of BCL10 and MALT1 in MT-2 cells. We previously highlighted that DMF suppressed the NF-ĸB signaling pathway in HTLV-1-infected MT-2 cells (19). However, the inhibitory mechanism was unknown.…”

Section: Resultsmentioning

confidence: 99%

“…phases in MT-2 cells. We previously demonstrated that DMF suppresses proliferation and cell death in MT-2 cells (19). We further explored the effects of DMF on the cell-cycle distribution in MT-2 cells (Figure 3).…”

Section: Dmf Induces Accumulation Of Cells In Sub-g 1 and S-/g 2 Mmentioning

confidence: 99%

“…In particular, DMF is an efficient inhibitor of NF-ĸB signaling in activated T-cells and different malignant cells such as melanoma, glioblastoma, cutaneous Tcell lymphoma, and diffuse large B-cell lymphoma (DLBCL) (13,17,18). We previously highlighted that DMF inhibits the activation (nuclear translocation) of NF-ĸB molecules in ATL cells (19). However, the specific mechanism of the inhibitory effect on NF-ĸB molecules remains unclear.…”

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confidence: 99%

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Dimethyl Fumarate Suppresses the Proliferation of HTLV-1-infected T Cells by Inhibiting CBM Complex-triggered NF-B Signaling

2023

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Background/Aim: Adult T-cell leukemia (ATL) is a peripheral T-lymphocytic malignancy influenced by human T-cell leukemia virus type 1 (HTLV-1) infection. AggressiveATL has a poor prognosis, therefore newer agents are desperately needed. We revealed that dimethyl fumarate (DMF) causes ATL cell death via inhibition of nuclear factor-kappa B (NF-ĸB) and signal transducer and activator of transcription 3 signaling. Here, we evaluated the specific mechanism of DMF effects on NF-ĸB signaling in MT-2 HTLV-1-infected T-cells. Materials and Methods: We examined the effects of DMF on the caspase recruitment domain family member 11 (CARD11)-BCL10 immune signaling adaptor (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (CBM) complex and upstream signaling molecules which are critical for NF-ĸB signaling in MT-2 cells by immunoblotting. We also explored its effects on cell-cycle distribution. Furthermore, we assessed whether the BCL2 apoptosis regulator (BCL2)/BCL2-like 1 (BCL-xL) inhibitor navitoclax promoted the inhibitory effect of DMF on cell proliferation and apoptosis-associated proteins by trypan blue exclusion test and immunoblotting, respectively. Results: DMF inhibited constitutive phosphorylation of CARD11 followed by suppression of inhibitory-ĸB kinase α/β phosphorylation at serine in a dose-dependent fashion in MT-2 cells. Furthermore, DMF inhibited MALT1 and BCL10 expression in the same fashion. However, DMF did not prevent the phosphorylation of protein kinase C-β, an upstream signaling molecule of CARD11. Cell-cycle analysis highlighted that DMF treatment at 75 μM resulted in the accumulation of cells at the sub-G 1 and G 2 /M phases. Navitoclax modestly promoted DMF-induced suppression of MT-2 cells via inhibition of cellular inhibitor of apoptosis protein-2 expression and c-JUN N-terminal kinase phosphorylation. Conclusion:The suppression of MT-2 cell proliferation by DMF makes its further evaluation as an innovative agent for therapy of ATL worthwhile.

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Section: Resultsmentioning

confidence: 99%

Section: Dmf Induces Accumulation Of Cells In Sub-g 1 and S-/g 2 Mmentioning

confidence: 99%

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confidence: 99%

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Dimethyl Fumarate Suppresses the Proliferation of HTLV-1-infected T Cells by Inhibiting CBM Complex-triggered NF-B Signaling

2023

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“…Of note, it has been reported that one of the most important therapeutic effects of DMF relies on its anti-inflammatory properties, which is why this drug has been registered for the treatment of inflammatory-based diseases such as psoriasis and multiple sclerosis [ 33 , 34 ]. Regarding cancer, previous studies have demonstrated the anti-cancer effects of DMF against several solid cancers [ 35 , 36 ] and hematologic cancers, including cutaneous T-cell lymphoma [ 37 ], diffuse large B cell lymphoma (DLBL), and HTLV-1-associated adult T cell leukemia [ 38 ]. At the molecular level, NF-kB was found to be inhibited by DMF and, in the latter two cancer types, the de-phosphorylation of STAT3 was also induced.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Sensitivity and Resistance of Primary Effusion Lymphoma to Dimethyl Fumarate (DMF)

Gonnella

Zarrella

Santarelli

et al. 2022

IJMS

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PEL is a rare B cell lymphoma associated with KSHV that mainly arises in immune-deficient individuals. The search for new drugs to treat this cancer is still ongoing given its aggressiveness and the poor response to chemotherapies. In this study, we found that DMF, a drug known for its anti-inflammatory properties which is registered for the treatment of psoriasis and relapsing–remitting MS, could be a promising therapeutic strategy against PEL. Indeed, although some mechanisms of resistance were induced, DMF activated NRF2, reduced ROS and inhibited the phosphorylation of STAT3 and the release of the pro-inflammatory and immune suppressive cytokines IL-6 and IL-10, which are known to sustain PEL survival. Interestingly, we observed that DMF displayed a stronger cytotoxic effect against fresh PEL cells in comparison to PEL cell lines, due to the activation of ERK1/2 and autophagy in the latter cells. This finding further encourages the possibility of using DMF for the treatment of PEL.

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“…The beneficial effects of DMF were also demonstrated in cancer. 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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Dimethyl Fumarate Induces ApoptosisviaInhibiting NF-κB and STAT3 Signaling in Adult T-cell Leukemia/Lymphoma Cells

Cited by 11 publications

References 0 publications

Dimethyl Fumarate Suppresses the Proliferation of HTLV-1-infected T Cells by Inhibiting CBM Complex-triggered NF-B Signaling

Dimethyl Fumarate Suppresses the Proliferation of HTLV-1-infected T Cells by Inhibiting CBM Complex-triggered NF-B Signaling

Mechanisms of Sensitivity and Resistance of Primary Effusion Lymphoma to Dimethyl Fumarate (DMF)

The Challenge of Dimethyl Fumarate Repurposing in Eye Pathologies

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