1β-hydroxyl-5α-chloro-8-epi-xanthatin (XTT), a sesquiterpene lactone isolated from Xanthium sibiricum, possessed potent cytotoxicity on cancer cells in vitro. The objective of this study was to investigate the anti-tumor effect and underlying mechanisms of XTT on human hepatocellular carcinoma (HCC). Firstly, XTT inhibited the cell growth and induced apoptosis in human HCC cells, which was associated with the induction of Bax and cleaved-caspase-3, inhibition of Bcl-2 and survivin expression. Importantly, XTT induced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), and depletion of glutathione (GSH) in HCC cells through covalently modification of GSH. Furthermore, XTT caused obvious activation of extracellular regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) and inactivation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) in HCC cells. ROS scavenger N-acetyl cysteine abrogated the effects of XTT on ERK/p38 MAPK activation and JAK2/STAT3 inhibition, and rescued HCC cells from XTT-induced apoptosis. Additionally, inhibitors of ERK/p38 MAPKs or activator of JAK2/STAT3 partially abolished XTT-mediated effect. In summary, XTT inhibited cell growth and induced apoptosis in HCC cells through ROS-mediated ERK/p38 MAPK activation and JAK2/STAT3 inhibition by GSH depletion. These findings also show the therapeutic potential of XTT in HCC.

中文翻译：

---

一种新的黄嘌呤类似物1β-羟基-5α-氯-8-表-黄嘌呤通过ROS介导的ERK / p38 MAPK激活和JAK2 / STAT3抑制作用诱导人肝细胞癌凋亡。

从黄柏中分离出的倍半萜内酯1β-羟基-5α-氯8-表-黄嘌呤（XTT）在体外对癌细胞具有强的细胞毒性。这项研究的目的是研究XTT对人类肝细胞癌（HCC）的抗肿瘤作用及其潜在机制。首先，XTT抑制人HCC细胞的生长并诱导其凋亡，这与诱导Bax和Caspase-3裂解，抑制Bcl-2和survivin表达有关。重要的是，XTT通过共价修饰GSH诱导HCC细胞中活性氧（ROS）和丙二醛（MDA）的生成以及谷胱甘肽（GSH）的消耗。此外，XTT导致HCC细胞中细胞外调节蛋白激酶（ERK）和p38丝裂原活化蛋白激酶（p38 MAPK）明显激活，而Janus激酶2 /信号转导子和转录激活子3（JAK2 / STAT3）失活。ROS清除剂N-乙酰半胱氨酸消除了XTT对ERK / p38 MAPK活化和JAK2 / STAT3抑制的作用，并从XTT诱导的凋亡中拯救了HCC细胞。此外，ERK / p38 MAPKs抑制剂或JAK2 / STAT3激活剂可部分消除XTT介导的作用。总之，XTT通过ROS介导的ERK / p38 MAPK活化和GSH耗竭抑制JAK2 / STAT3抑制HCC细胞的生长并诱导其凋亡。这些发现还显示了XTT在肝癌中的治疗潜力。ROS清除剂N-乙酰半胱氨酸消除了XTT对ERK / p38 MAPK活化和JAK2 / STAT3抑制的作用，并从XTT诱导的凋亡中拯救了HCC细胞。此外，ERK / p38 MAPKs抑制剂或JAK2 / STAT3激活剂可部分消除XTT介导的作用。总之，XTT通过ROS介导的ERK / p38 MAPK活化和GSH耗竭抑制JAK2 / STAT3抑制HCC细胞的生长并诱导其凋亡。这些发现还显示了XTT在肝癌中的治疗潜力。ROS清除剂N-乙酰半胱氨酸消除了XTT对ERK / p38 MAPK活化和JAK2 / STAT3抑制的作用，并从XTT诱导的凋亡中拯救了HCC细胞。此外，ERK / p38 MAPKs抑制剂或JAK2 / STAT3激活剂可部分消除XTT介导的作用。总之，XTT通过ROS介导的ERK / p38 MAPK活化和GSH耗竭抑制JAK2 / STAT3抑制HCC细胞的生长并诱导其凋亡。这些发现还显示了XTT在肝癌中的治疗潜力。XTT通过ROS介导的ERK / p38 MAPK活化和GSH耗竭抑制JAK2 / STAT3抑制HCC细胞的生长并诱导其凋亡。这些发现还显示了XTT在肝癌中的治疗潜力。XTT通过ROS介导的ERK / p38 MAPK活化和GSH耗竭抑制JAK2 / STAT3抑制HCC细胞的生长并诱导其凋亡。这些发现还显示了XTT在肝癌中的治疗潜力。