Shi Xiao-Jing, Ding Lina, Zhou Wenjuan, Ji Yage, Wang Junwei, Wang Huimin, Ma Yongcheng, Jiang Guozhong, Tang Kai, Ke Yu, Zhao Wen, Liu Hong-Min
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
Antioxid Redox Signal. 2017 Jul 10;27(2):73-92. doi: 10.1089/ars.2016.6703. Epub 2016 Nov 1.
Esophageal cancer (EC) is an aggressive malignancy and the most common solid tumor of gastrointestinal tract all over the world, with high incidence in Asia. The current study was designed to investigate the anticancer efficacy and mechanism that is involved in the action of a natural ent-kaurene diterpenoid, JDA-202, targeting EC.
We found that an antioxidant protein peroxiredoxin I (Prx I) was upregulated in human EC tissues as well as in EC cell lines. JDA-202, a novel natural compound isolated from Isodon rubescens (Labiatae), was proved to possess strong anti-proliferative activities on those cell lines. Importantly, JDA-202 does not only bind to Prx I directly and markedly inhibit the activity of Prx I in vitro, but it also significantly induces hydrogen peroxide (HO)-related cell death. Furthermore, overexpression of Prx I significantly reversed EC109 cell apoptosis caused by JDA-202, whereas short interfering RNA (siRNA)-induced Prx I knockdown resulted in marked cell death even without JDA-202 pretreatment. On the other hand, the increased phosphorylation of mitogen-activated protein kinase (MAPK) proteins (c-Jun N-terminal kinase [JNK], p38, and extracellular signal-regulated kinase [ERK]) by JDA-202 was suppressed by N-acetylcysteine (NAC) or catalase, a known reactive oxygen species (ROS) or HO scavenger. JDA-202 also significantly inhibited the growth of EC109 tumor xenograft, without significant body weight loss and multi-organ toxicities. Innovation and Conclusion: Our findings, for the first time, demonstrated that JDA-202 may serve as a lead compound, targeting the overexpressed Prx I in EC cell lines and ROS accumulation as well as inhibiting the activation of their downstream targets in MAPKs. Antioxid. Redox Signal. 27, 73-92.
食管癌（EC）是一种侵袭性恶性肿瘤，是全球最常见的胃肠道实体瘤，在亚洲发病率很高。本研究旨在探讨天然贝壳杉烯二萜类化合物JDA-202对EC的抗癌疗效及其作用机制。
我们发现抗氧化蛋白过氧化物酶I（Prx I）在人EC组织和EC细胞系中均上调。从冬凌草（唇形科）中分离出的一种新型天然化合物JDA-202，被证明对这些细胞系具有强大的抗增殖活性。重要的是，JDA-202不仅能直接结合Prx I并在体外显著抑制Prx I的活性，还能显著诱导过氧化氢（H₂O₂）相关的细胞死亡。此外，Prx I的过表达显著逆转了JDA-202引起的EC109细胞凋亡，而短干扰RNA（siRNA）诱导的Prx I敲低即使在没有JDA-202预处理的情况下也会导致明显的细胞死亡。另一方面，JDA-202引起的丝裂原活化蛋白激酶（MAPK）蛋白（c-Jun氨基末端激酶[JNK]、p38和细胞外信号调节激酶[ERK]）磷酸化增加被N-乙酰半胱氨酸（NAC）或过氧化氢酶（一种已知的活性氧[ROS]或H₂O₂清除剂）所抑制。JDA-202还显著抑制了EC109肿瘤异种移植瘤的生长，且没有明显的体重减轻和多器官毒性。创新与结论：我们的研究结果首次表明，JDA-202可能作为一种先导化合物，靶向EC细胞系中过表达的Prx I和ROS积累，并抑制其MAPKs下游靶点的激活。《抗氧化与氧化还原信号》27卷，73 - 92页。
