a Chemical Biology Research Center, School of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , China.
b Department of Digestive Diseases , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , China.
Free Radic Res. 2019 Jan;53(1):104-114. doi: 10.1080/10715762.2018.1558448. Epub 2019 Feb 4.
Thioredoxin reductase 1 (TrxR1) has emerged as a potential target for cancer therapy, because it is overexpressed in several types of cancers and associated with increased tumour growth and poor patient prognosis. Alantolactone (ALT), a natural sesquiterpene lactone originated from traditional folk medicine Inula helenium L., has been reported to exert antitumor activity in various tumours. However, the effect of ALT on human gastric cancer cells and its underlying mechanism remains unknown. In this study, we showed that ALT inhibited cell proliferation and induced cell apoptosis in gastric cancer cells. Mechanistically, our data found that ALT induced reactive oxygen species (ROS) production by inhibiting TrxR1 activity, resulting in the activation of p38 mitogen-activated protein kinase (MAPK) pathway and eventually cell apoptosis in gastric cancer cells. And the effects of ALT were reversed by pre-treatment with NAC (a scavenger of ROS). Further investigation revealed that ALT displayed synergistic lethality with erastin against gastric cancer cells, which demonstrating combined inhibition of TrxR1 and glutathione (GSH) leads to a synergistic effect in gastric cancer cells. More importantly, ALT treatment markedly reduced the activity of TrxR1 in vivo and inhibited the growth of gastric cancer xenografts without exhibiting significant toxicity. Taken together, these findings suggest that ALT may be used as a novel therapeutic agent against human gastric cancer.
硫氧还蛋白还原酶 1（TrxR1）已成为癌症治疗的潜在靶点，因为它在几种类型的癌症中过度表达，与肿瘤生长增加和患者预后不良有关。冬凌草甲素（ALT）是一种源自传统民间医学旋覆花的天然倍半萜内酯，已被报道在各种肿瘤中具有抗肿瘤活性。然而，ALT 对人胃癌细胞的作用及其潜在机制尚不清楚。在本研究中，我们表明 ALT 抑制了胃癌细胞的增殖并诱导了细胞凋亡。在机制上，我们的数据发现 ALT 通过抑制 TrxR1 活性诱导活性氧（ROS）的产生，导致 p38 丝裂原活化蛋白激酶（MAPK）途径的激活，最终导致胃癌细胞凋亡。并且 ALT 的作用可以通过用 NAC（ROS 的清除剂）预处理来逆转。进一步的研究表明，ALT 与 erastin 对胃癌细胞表现出协同致死作用，这表明联合抑制 TrxR1 和谷胱甘肽（GSH）可导致胃癌细胞产生协同作用。更重要的是，ALT 处理显著降低了体内 TrxR1 的活性并抑制了胃癌异种移植物的生长，而没有表现出明显的毒性。总之，这些发现表明 ALT 可能被用作治疗人类胃癌的新型治疗剂。
