PubAg

Main content area

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

Author:
Wang, Bei, Zhou, Tan-Yang, Nie, Chun-Hui, Wan, Da-Long, Zheng, Shu-Sen
Source:
Biochemical and biophysical research communications 2018 v.499 no.2 pp. 156-163
ISSN:
0006-291X
Subject:
Inula, NAD ADP-ribosyltransferase, acetylcysteine, antineoplastic activity, antineoplastic agents, apoptosis, autophagy, caspase-3, cell lines, cell proliferation, dose response, humans, in vivo studies, liver neoplasms, non-specific serine/threonine protein kinase, phosphorylation, rapamycin, sesquiterpenoids, toxicity
Abstract:
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.
Agid:
5925361