Chen Kaiyuan, Wu Shanshan, Ye Sisi, Huang Huimin, Zhou Yi, Zhou Hongfei, Wu Shijia, Mao Yefan, Shangguan Fugen, Lan Linhua, Chen Bicheng
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Laboratory of Precision Medical Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Front Pharmacol. 2021 Feb 22;12:617714. doi: 10.3389/fphar.2021.617714. eCollection 2021.
Dimethyl fumarate (DMF) is an approved drug used in the treatment of multiple sclerosis (MS) and psoriasis therapy. Multiple studies have demonstrated other pharmacological activities of DMF such as an anti-cancer agent. In particular, studies have shown that DMF can modulate the NRF2/HO1/NQO1 antioxidant signal pathway and inactivate NF-κB to suppress the growth of colon and breast cancer cells, and induce cell death. In this study, we aimed to evaluate the anti-tumor activities of DMF in pancreatic cancer (PC) focusing on cell death as the predominant mechanism of response. We showed that both mitochondrial respiration and aerobic glycolysis were severely depressed following treatment with DMF and the effects could be abrogated by treatment with L-cysteine and N-acetyl-L-cysteine (NAC). Importantly, we verified that DMF induced metabolic crisis and that cell death was not related to alterations in ROS. Our data implied that MTHFD1 could be a potential downstream target of DMF identified by molecular docking analysis. Finally, we confirmed that MTHFD1 is up-regulated in PC and overexpression of MTHFD1 was negatively related to outcomes of PC patients. Our data indicate that DMF induces metabolic crisie to suppress cell growth and could be a potential novel therapy in the treatment of PC.
富马酸二甲酯（DMF）是一种已获批用于治疗多发性硬化症（MS）和银屑病的药物。多项研究已证明DMF具有其他药理活性，如作为抗癌剂。特别是，研究表明DMF可调节NRF2/HO1/NQO1抗氧化信号通路并使NF-κB失活，以抑制结肠和乳腺癌细胞的生长，并诱导细胞死亡。在本研究中，我们旨在评估DMF在胰腺癌（PC）中的抗肿瘤活性，重点关注细胞死亡作为主要反应机制。我们发现，用DMF处理后，线粒体呼吸和有氧糖酵解均受到严重抑制，而用L-半胱氨酸和N-乙酰-L-半胱氨酸（NAC）处理可消除这些影响。重要的是，我们证实DMF诱导了代谢危机，且细胞死亡与ROS的改变无关。我们的数据表明，MTHFD1可能是通过分子对接分析确定的DMF潜在下游靶点。最后，我们证实MTHFD1在PC中上调，且MTHFD1的过表达与PC患者的预后呈负相关。我们的数据表明，DMF诱导代谢危机以抑制细胞生长，可能是治疗PC的一种潜在新疗法。
