Che Yun, Wang Jingnan, Yuan Zuyang, Li Yuan, Lu Zhiliang, Zhang Zhirong, Zhang Jinyao, Wan Jun, Sun Handong, Chen Zhaoli, Pu Jianxin, He Jie
Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
Toxicol Lett. 2017 Oct 5;280:106-115. doi: 10.1016/j.toxlet.2017.08.005. Epub 2017 Aug 8.
Effective treatments for esophageal squamous cell carcinoma (ESCC), one of the most common cancers in China, are lacking. Longikaurin A (LK-A), an ent-kauranoid diterpenoid isolated from Isodon ternifolius, has been shown to have potent cytotoxic effects on ESCC cells both in vivo and in vitro, mainly by inducing apoptosis. In this study, LK-A inhibited ESCC cells viability and induced G2/M cell cycle arrest. Moreover, LK-A was also highly effective in a KYSE-30 xenograft nude mouse model. Treatment with Z-VAD(OMe)-FMK partially attenuated LK-A-induced apoptosis. LK-A significantly induced reactive oxygen species (ROS) production in ESCC cells, and LK-A-induced apoptosis was attenuated by the ROS scavenger N-acetyl cysteine (NAC). Furthermore, we found that treatment with LK-A activated both the JNK and p38 MAPK signaling pathways, resulting in increases in ROS levels and apoptosis induction. Taken together, these findings indicate that LK-A exerts novel anti-tumor effects in ESCC cells by activating the JNK and p38 MAPK pathways and inducing increases in ROS production, which suggest that the compound may have potential as a clinical therapeutic agent.
中国最常见的癌症之一——食管鳞状细胞癌（ESCC）缺乏有效的治疗方法。长叶牛膝菊内酯A（LK-A）是从三叶香茶菜中分离出的一种对映贝壳杉烷型二萜类化合物，已被证明在体内和体外对ESCC细胞均具有强大的细胞毒性作用，主要是通过诱导细胞凋亡。在本研究中，LK-A抑制了ESCC细胞的活力并诱导了G2/M期细胞周期阻滞。此外，LK-A在KYSE-30异种移植裸鼠模型中也非常有效。用Z-VAD(OMe)-FMK处理可部分减弱LK-A诱导的细胞凋亡。LK-A显著诱导ESCC细胞中活性氧（ROS）的产生，而ROS清除剂N-乙酰半胱氨酸（NAC）可减弱LK-A诱导的细胞凋亡。此外，我们发现用LK-A处理可激活JNK和p38 MAPK信号通路，导致ROS水平升高和细胞凋亡诱导。综上所述，这些发现表明LK-A通过激活JNK和p38 MAPK通路并诱导ROS产生增加，在ESCC细胞中发挥新的抗肿瘤作用，这表明该化合物可能具有作为临床治疗药物的潜力。
