Department of Development, Reproduction and Cancer, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.
Division of Molecular Medicine, Institut Ruđer Bošković, Zagreb, Croatia.
Med Res Rev. 2019 Sep;39(5):1923-1952. doi: 10.1002/med.21567. Epub 2019 Feb 12.
Dimethyl fumarate (DMF) is a fumaric acid ester registered for the treatment of relapsing-remitting multiple sclerosis (RRMS). It induces protein succination leading to inactivation of cysteine-rich proteins. It was first shown to possess cytoprotective and antioxidant effects in noncancer models, which appeared related to the induction of the nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) pathway. DMF also displays antitumor activity in several cellular and mice models. Recently, we showed that the anticancer mechanism of DMF is dose-dependent and is paradoxically related to the decrease in the nuclear translocation of NRF2. Some other studies performed indicate also the potential role of DMF in cancers, which are dependent on the NRF2 antioxidant and cellular detoxification program, such as KRAS-mutated lung adenocarcinoma. It, however, seems that DMF has multiple biological effects as it has been shown to also inhibit the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thus blocking downstream targets that may be involved in the development and progression of inflammatory cascades leading to various disease processes, including tumors, lymphomas, diabetic retinopathy, arthritis, and psoriasis. Herein, we present the current status and future directions of the use of DMF in various diseases models with particular emphases on its targeting of specific intracellular signal transduction cascades in cancer; to shed some light on its possible mode of action.
富马酸二甲酯（DMF）是一种已注册用于治疗复发缓解型多发性硬化症（RRMS）的富马酸酯。它诱导蛋白质琥珀酰化，导致富含半胱氨酸的蛋白质失活。最初在非癌症模型中发现其具有细胞保护和抗氧化作用，这似乎与核因子红细胞 2（NF-E2）相关因子 2（NRF2）途径的诱导有关。DMF 还在几种细胞和小鼠模型中表现出抗肿瘤活性。最近，我们表明 DMF 的抗癌机制是剂量依赖性的，与 NRF2 的核转位减少相反。其他一些研究也表明了 DMF 在癌症中的潜在作用，这些癌症依赖于 NRF2 抗氧化和细胞解毒程序，例如 KRAS 突变型肺腺癌。然而，DMF 似乎具有多种生物学效应，因为它已被证明还可以抑制转录因子核因子κ轻链增强子激活的 B 细胞（NF-κB），从而阻断下游靶点，这些靶点可能参与炎症级联的发展和进展，导致各种疾病过程，包括肿瘤、淋巴瘤、糖尿病性视网膜病变、关节炎和银屑病。在此，我们介绍了 DMF 在各种疾病模型中的应用现状和未来方向，特别强调了其在癌症中针对特定细胞内信号转导级联的作用；阐明其可能的作用模式。
