Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
Biochem Biophys Res Commun. 2018 May 5;499(2):156-163. doi: 10.1016/j.bbrc.2018.03.091. Epub 2018 Mar 22.
Bigelovin (BigV) is a sesquiterpene lactone, isolated from Inula helianthus aquatica, which has been reported to induce apoptosis and show anti-inflammatory and anti-angiogenic activities. Nevertheless, the effects of BigV on liver cancer and the underlying mechanisms have not been investigated. In the study, we found that BigV exhibited potential anti-tumor activities against human liver cancer in vitro and in vivo. BigV reduced the cell proliferation and colony formation. BigV induced apoptosis through improving the cleavage of Caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1). The process was along with the activation of autophagy, as proved by the enhanced accumulation of autophagosomes, the microtubule-associated light chain 3B-II (LC3B-II) and Beclin-1, and p62 decrease. Further, the autophagy blockage markedly sensitized BigV-induced cell death, indicating the cytoprotective function of autophagy in liver cancer cell lines. In addition, BigV treatment inactivated the pathway of protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K). Of note, BigV-induced cell death was abolished by over-expressing the phosphorylation of mTOR. Intriguingly, the induction of apoptosis and autophagy were eliminated by the pretreatment of reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC), suggesting that ROS played an important role in the regulation of BigV-induced cell death. Finally, in vivo studies demonstrated that BigV significantly suppressed the growth of HepG2 cancer xenograft tumors through the activation of apoptosis and autophagy in a dose-dependent manner with low systemic toxicity. In conclusion, the results revealed that BigV had significant antitumor effects against human liver cancer and it may potentially be used as a novel antitumor agent for the prevention of liver cancer.
大花旋覆花内酯（BigV）是一种倍半萜内酯，从土木香黄花中分离得到，已报道其具有诱导细胞凋亡、抗炎和抗血管生成活性。然而，BigV 对肝癌的作用及其潜在机制尚未得到研究。在这项研究中，我们发现 BigV 在体外和体内均对人肝癌具有潜在的抗肿瘤活性。BigV 降低了细胞增殖和集落形成。BigV 通过提高 Caspase-3 和多聚（ADP-核糖）聚合酶 1（PARP-1）的裂解诱导细胞凋亡。这一过程伴随着自噬的激活，这一点可通过自噬体、微管相关轻链 3B-II（LC3B-II）和 Beclin-1 的积累增加以及 p62 的减少得到证明。此外，自噬阻断明显增强了 BigV 诱导的细胞死亡，表明自噬在肝癌细胞系中具有细胞保护作用。此外，BigV 处理可使蛋白激酶 B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）/核糖体蛋白 S6 激酶（p70S6K）通路失活。值得注意的是，过表达 mTOR 的磷酸化可消除 BigV 诱导的细胞死亡。有趣的是，用活性氧（ROS）清除剂 N-乙酰-L-半胱氨酸（NAC）预处理可消除细胞凋亡和自噬的诱导，表明 ROS 在调节 BigV 诱导的细胞死亡中发挥了重要作用。最后，体内研究表明，BigV 通过激活凋亡和自噬，以剂量依赖的方式显著抑制 HepG2 肝癌异种移植瘤的生长，且全身毒性低。总之，研究结果表明 BigV 对人肝癌具有显著的抗肿瘤作用，可能作为预防肝癌的新型抗肿瘤药物。
