Dimethyl Fumarate Combined With Vemurafenib Enhances Anti-Melanoma Efficacy via Inhibiting the Hippo/YAP, NRF2-ARE, and AKT/mTOR/ERK Pathways in A375 Melanoma Cells

Wang, Yaping; Su, Rina; Jia, Yanjie; Xiong, Li; Fan, Yaochun; Wang, Yuewu; Xing, Wanjin; Qin, Jian‐Zhong

doi:10.3389/fonc.2022.794216

Cited by 12 publications

(16 citation statements)

References 66 publications

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“…Given that STAT3 was de-phosphorylated by DMF at both 20 and 50 µM doses, particularly in BC3 cells, we then evaluated whether the activation of pro-survival pathway(s) could counteract its cytotoxic effect when used at the lower dose of 20 µM. We investigated the phosphorylation of 4EBP1 (an mTOR target), as the activation of this pathway sustains PEL cell survival [ 19 ] and can be influenced by DMF treatment [ 23 ]. As shown in Figure 2 A, at 20 µM dose, p-4EBP1 was hyperactivated by DMF in both BC3 and BCBL1 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, STAT3 has also been reported to be among the pathways inhibited by DMF, e.g., in hepatocellular carcinoma [ 22 ]. AKT/mTOR/ERK signaling has also been shown to be inhibited by DMF in melanoma cells when used in combination with Vemurafenib [ 23 ]. Based on this collection of evidence and the anti-inflammatory activity of DMF, in this study, we investigated the possibility of treating PEL cell lines and fresh PEL cells with this drug.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

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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“…In addition, DMF had no effect on the cytotoxicity of paclitaxel and adriamycin to MCF10A cells. DMF enhances the anti-melanoma efficacy of vemurafenib, a BRAF inhibitor, by suppressing multiple signaling pathways [ 19 ]. In a phase I clinical trial of DMF in combination with temozolomide and radiotherapy in patients with glioblastoma, a dose of 240 mg three times daily was reported to be safe and well tolerated by patients, with partial responses observed in 4 of 12 patients [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Dimethyl Fumarate Induces Apoptosis via Inhibition of NF-κB and Enhances the Effect of Paclitaxel and Adriamycin in Human TNBC Cells

Tsubaki

Takeda

Matsuda

et al. 2022

IJMS

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Triple-negative breast cancer (TNBC) has the poorest prognosis of all breast cancer subtypes. Recently, the activation of NF-κB, which is involved in the growth and survival of malignant tumors, has been demonstrated in TNBC, suggesting that NF-κB may serve as a new therapeutic target. In the present study, we examined whether dimethyl fumarate (DMF), an NF-κB inhibitor, induces apoptosis in TNBC cells and enhances the apoptosis-inducing effect of paclitaxel and adriamycin. Cell survival was analyzed by the trypan blue assay and apoptosis assay. Protein detection was examined by immunoblotting. The activation of NF-κB p65 was correlated with poor prognosis in patients with TNBC. DMF induced apoptosis in MDA-MB-231 and BT-549 cells at concentrations that were non-cytotoxic to the normal mammary cell line MCF-10A. Furthermore, DMF inhibited NF-κB nuclear translocation and Survivin, XIAP, Bcl-xL, and Bcl-2 expression in MDA-MB-231 and BT-549 cells. Moreover, DMF enhanced the apoptosis-inducing effect of paclitaxel and adriamycin in MDA-MB-231 cells. These findings suggest that DMF may be an effective therapeutic agent for the treatment of TNBC, in which NF-κB is constitutively active. DMF may also be useful as an adjuvant therapy to conventional anticancer drugs.

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“…The combination of DMF with vemurafenib significantly reduced melanoma cell growth and increased tumor cell death in vitro and in vivo. A combination of DMF and vemurafenib could be a novel therapeutic method against melanoma [ 54 ] Argenziano et al, 2022 M14 melanoma cell line The Nrf2 protein level was downregulated after the treatment of M14 cells with siNrf2-NB. Subsequently, the treated cells showed significant downregulation of the viability cells.…”

Section: Methodsmentioning

confidence: 99%

The dual role of Nrf2 in melanoma: a systematic review

Malakoutikhah

Mohajeri

Dana

et al. 2023

BMC Mol and Cell Biol

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Melanoma is the most lethal type of skin cancer that originates from the malignant transformation of melanocytes. Although novel treatments have improved patient survival in melanoma, the overall prognosis remains poor. To improve current therapies and patients outcome, it is necessary to identify the influential elements in the development and progression of melanoma.Due to UV exposure and melanin synthesis, the melanocytic lineage seems to have a higher rate of ROS (reactive oxygen species) formation. Melanoma has been linked to an increased oxidative state, and all facets of melanoma pathophysiology rely on redox biology. Several redox-modulating pathways have arisen to resist oxidative stress. One of which, the Nrf2 (nuclear factor erythroid 2-related factor 2), has been recognized as a master regulator of cellular response to oxidative or electrophilic challenges. The activation of Nrf2 signaling causes a wide range of antioxidant and detoxification enzyme genes to be expressed. As a result, this transcription factor has lately received a lot of interest as a possible cancer treatment target.On the other hand, Nrf2 has been found to have a variety of activities in addition to its antioxidant abilities, constant Nrf2 activation in malignant cells may accelerate metastasis and chemoresistance. Hence, based on the cell type and context, Nrf2 has different roles in either preventing or promoting cancer. In this study, we aimed to systematically review all the studies discussing the function of Nrf2 in melanoma and the factors determining its alteration.

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Dimethyl Fumarate Combined With Vemurafenib Enhances Anti-Melanoma Efficacy via Inhibiting the Hippo/YAP, NRF2-ARE, and AKT/mTOR/ERK Pathways in A375 Melanoma Cells

Cited by 12 publications

References 66 publications

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

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

Dimethyl Fumarate Induces Apoptosis via Inhibition of NF-κB and Enhances the Effect of Paclitaxel and Adriamycin in Human TNBC Cells

The dual role of Nrf2 in melanoma: a systematic review

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