Bigelovin, a sesquiterpene lactone, suppresses tumor growth through inducing apoptosis and autophagy via the inhibition of mTOR pathway regulated by ROS generation in liver cancer

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.