Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, PR China.
Thoracic Surgery, The Second Hospital of Jilin University, Changchun 130041, PR China.
Toxicol Appl Pharmacol. 2018 Aug 1;352:46-58. doi: 10.1016/j.taap.2018.05.026. Epub 2018 May 22.
Esophageal cancer is the eighth most prevalent cancer and has high mortality in our society. Isoalantolactone, extracted from Inula helenium L, has shown potent anticancer effects on a variety of cancers. However, its effect on human esophageal cancer, and the underlying molecular mechanism, remain to be investigated. In the present study, we demonstrated that isoalantolactone induced apoptosis in esophageal cancer cells. Treatment with isoalantolactone activated caspases-3, -7, and -10, and upregulated death receptor (DR)5. Furthermore, DR5 knockdown partially reversed the effect of isoalantolactone. These results indicated the extrinsic apoptosis was induced by isoalantolactone. In addition, intracellular reactive oxygen species (ROS) were significantly elevated after treatment with isoalantolactone. N-Acetylcysteine, an ROS scavenger, blocked both the apoptosis and decreased cell viability caused by isoalantolactone. In vivo, significant suppression of tumor growth by isoalantolactone was observed in an ECA109 cell xenograft mouse model. Isoalantolactone showed no obvious adverse effects on mouse weight and histology of heart, liver, spleen, lung, and kidney. In conclusion, our results revealed that isoalantolactone induced apoptosis through the extrinsic pathway via upregulation of DR5 and elevation of ROS in human esophageal cancer cells. Isoalantolactone, therefore, could be a potential candidate in developing anticancer agents for esophageal cancer patients.
食管癌是全球第八大常见癌症，死亡率较高。土木香内酯是土木香中提取的一种化合物，已被证明对多种癌症具有强大的抗癌作用。然而，它对人食管癌的作用及其潜在的分子机制仍需进一步研究。本研究表明，土木香内酯可诱导食管癌细胞凋亡。土木香内酯处理可激活半胱氨酸天冬氨酸蛋白酶（caspase）-3、-7 和 -10，并上调死亡受体 5（DR5）。此外，DR5 敲低部分逆转了土木香内酯的作用。这些结果表明，土木香内酯诱导了细胞的外在凋亡途径。此外，土木香内酯处理后细胞内活性氧（ROS）显著增加。ROS 清除剂 N-乙酰半胱氨酸（N-acetylcysteine）可阻断土木香内酯引起的细胞凋亡和细胞活力下降。在体内，土木香内酯在 ECA109 细胞异种移植小鼠模型中显著抑制肿瘤生长。土木香内酯对小鼠体重及心、肝、脾、肺、肾组织学无明显不良影响。总之，本研究结果表明，土木香内酯通过上调 DR5 和增加 ROS 水平，诱导人食管癌细胞发生外在途径的细胞凋亡。因此，土木香内酯可能成为开发食管癌治疗药物的潜在候选药物。
