Takeda Tomoya, Tsubaki Masanobu, Asano Ryota, Itoh Tatsuki, Imano Motohiro, Satou Takao, Nishida Shozo
Division of Pharmacotherapy, Kindai University School of Pharmacy, Osaka, Japan.
Department of Food Science and Nutrition, Kindai University School of Agriculture, Nara, Japan.
J Dermatol Sci. 2020 Sep;99(3):168-176. doi: 10.1016/j.jdermsci.2020.07.004. Epub 2020 Jul 16.
Malignant melanoma is among the deadliest forms of skin cancers, and its incidence has been increasing over the past decades. In malignant melanoma, activation of the nuclear factor kappa B (NF-κB) promotes survival, migration, and invasion of cancer cells. Anti-NF-κB agents for treating metastatic melanoma would be beneficial, but no such drug is approved as either monotherapy or adjuvant therapy. Dimethyl fumarate (DMF) is an approved anti-inflammatory drug already in clinical use for psoriasis and multiple sclerosis.
We investigated the anti-tumour effect of DMF treatment in metastatic melanoma in vitro and in vivo.
The cell viability was assessed via trypan blue exclusion assay. The migration and invasion was analyzed in a Boyden chamber assay. The anti-metastatic effects and anti-tumour activity of DMF was determined in an in-vivo model. The expressions of NF-κB pathway and NF-κB regulatory proteins were detected via western blotting.
DMF decreased the cell viability, migration and invasion in vitro. In addition, DMF inhibited spontaneous metastasis and tumour growth. Mechanistically, DMF prevented the nuclear translocation of NF-κB, whereas no changes were observed in the phosphorylation levels of inhibitor of kappa B (IκB). In addition, DMF inhibited the expression of matrix metalloproteinases (MMPs) and very late antigens (VLAs). Furthermore, DMF treatment decreased the expression of Survivin and Bcl-extra large (Bcl-XL) proteins.
Our results suggest that DMF as a novel inhibitor of NF-κB may be a potential therapeutic agent for metastatic melanoma.
恶性黑色素瘤是最致命的皮肤癌形式之一，在过去几十年中其发病率一直在上升。在恶性黑色素瘤中，核因子κB（NF-κB）的激活促进癌细胞的存活、迁移和侵袭。用于治疗转移性黑色素瘤的抗NF-κB药物将是有益的，但尚无此类药物被批准用于单一疗法或辅助疗法。富马酸二甲酯（DMF）是一种已获批准的抗炎药物，已在临床上用于治疗银屑病和多发性硬化症。
我们研究了DMF治疗对转移性黑色素瘤的体外和体内抗肿瘤作用。
通过台盼蓝排斥试验评估细胞活力。在Boyden小室试验中分析迁移和侵袭情况。在体内模型中确定DMF的抗转移作用和抗肿瘤活性。通过蛋白质印迹法检测NF-κB信号通路和NF-κB调节蛋白的表达。
DMF在体外降低了细胞活力、迁移和侵袭能力。此外，DMF抑制了自发转移和肿瘤生长。从机制上讲，DMF阻止了NF-κB的核转位，而κB抑制蛋白（IκB）的磷酸化水平未观察到变化。此外，DMF抑制了基质金属蛋白酶（MMPs）和极晚期抗原（VLAs）的表达。此外，DMF治疗降低了生存素和Bcl-超大蛋白（Bcl-XL）的表达。
我们的结果表明，DMF作为一种新型的NF-κB抑制剂可能是转移性黑色素瘤的潜在治疗药物。
