The alcohol-averse drug disulfiram has been reported to have anti-tumor effects and is well suited for drug combinations. In order to identify potential drug combinations in esophageal squamous cell carcinoma (ESCC), we screened a bioactive compound library with the disulfiram copper chelation product CuET. The Jumonji domain-containing protein 3 (JMJD3) and the ubiquitously transcribed tetratricopeptide repeat protein X-linked (UTX) inhibitor GSK J4 were identified. To further understand the molecular mechanism underlying the efficient drug combination, we applied quantitative mass spectrometry to analyze the signaling pathway perturbation after drug treatment. The data revealed that the synergistic effect of GSK J4 and CuET was due to the interaction among JMJD3 and UTX, which may play important roles in maintaining endoplasmic reticulum (ER) homeostasis in tumor cells. Interestingly, our clinical data analysis showed that high expression of JMJD3 and UTX was associated with T stage and worse prognosis of ESCC patients, further supporting the importance of the above findings. In conclusion, our findings suggest that the combination of CuET and targeting JMJD3/UTX may be a safe, effective, and available treatment for ESCC.
据报道，具有酒精厌恶作用的药物双硫仑具有抗肿瘤效应，且非常适合用于药物联合治疗。为探索食管鳞状细胞癌（ESCC）中潜在的药物组合方案，我们利用双硫仑铜螯合产物CuET对生物活性化合物库进行了筛选，并鉴定出含Jumonji结构域蛋白3（JMJD3）与泛表达四肽重复序列X连锁蛋白（UTX）的抑制剂GSK J4。为深入理解该有效药物组合的分子机制，我们采用定量质谱技术分析了药物治疗后的信号通路扰动情况。数据显示，GSK J4与CuET的协同效应源于JMJD3与UTX之间的相互作用，二者可能在维持肿瘤细胞内质网（ER）稳态中发挥重要作用。值得注意的是，临床数据分析显示JMJD3与UTX的高表达与ESCC患者的T分期及不良预后相关，进一步佐证了上述发现的重要性。综上所述，本研究提示CuET联合靶向JMJD3/UTX可能成为ESCC一种安全、有效且可及的治疗策略。
肿瘤(癌症)患者之家