Inhibition of PI3K/Akt/mTOR pathway by apigenin induces apoptosis and autophagy in hepatocellular carcinoma cells.

Apigenin is a dietary flavonoid with known antioxidant and antitumor effects against several types of cancers by promoting cell death and inducing cell cycle arrest. Apigenin also regulates a variety of intracellular signal transduction pathways during apoptosis or autophagy. However, the precise mechanism underlying the anticancer effects of apigenin in liver cancer remains poorly understood. In this study, we demonstrated that apigenin has anticancer activity against hepatocellular carcinoma cells. Apigenin inhibited the cell growth and induced cell death in a dose- and time-dependent manner in HepG2 cells. We found that apigenin treatment increased the expression of LC3-II and the number of GFP-LC3 puncta. Moreover, inhibition of autophagy with 3-MA and Atg5 gene silencing strengthened apigenin-induced proliferation inhibition and apoptosis. Our data has indicated that apigenin-induced autophagy has a protective effect against cell death. Additionally, apigenin induced apoptosis and autophagy through inhibition of PI3K/Akt/mTOR pathway. Most importantly, in vivo data showed that administration of apigenin decreased tumor growth and autophagy inhibition by 3-MA significantly enhanced the anticancer effect of apigenin. Collectively, our results reveal that apigenin inhibits cell proliferation and induces autophagy via suppressing the PI3K/Akt/mTOR pathway. Our results also suggest combination of autophagy inhibitors and apigenin would be a potential chemotherapeutic strategy against hepatocellular carcinoma.

Yang J ，Pi C ，Wang G 《-》

Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway.

Zhang DM ，Liu JS ，Deng LJ ，Chen MF ，Yiu A ，Cao HH ，Tian HY ，Fung KP ，Kurihara H ，Pan JX ，Ye WC ... -  《-》

Comprehensive anti-tumor effect of Brusatol through inhibition of cell viability and promotion of apoptosis caused by autophagy via the PI3K/Akt/mTOR pathway in hepatocellular carcinoma.

Brusatol, a natural quassinoid isolated from a traditional Chinese herbal medicine known as Bruceae Fructus, has recently been reported to possess powerful cytotoxic effects against various cancer cell lines, highlighting its potential as an anti-cancer drug. However, the precise molecular mechanisms by which Brusatol exerts its anti-cancer effects remain poorly understood in hepatocellular carcinoma (HCC). In this study, we demonstrated that Brusatol inhibited cell viability, proliferation and induced apoptosis in liver cancer lines. Furthermore, Brusatol could activate autophagy in diverse liver cell lines, and the autophagy inhibitor chloroquine (CQ) reversed Brusatol-induced apoptosis in Bel7404 cells. In addition, we found that Brusatol inhibited PI3K/Akt/mTOR. Brusatol may also inhibit invasion, migration and the epithelial-mesenchymal transition (EMT). In a human liver xenograft tumor model in nude mice, immunohistochemistry showed that Brusatol significantly inhibited tumor invasion and proliferation. Taken together, these results revealed that Brusatol effectively inhibited proliferation and induced apoptosis in HCC through autophagy induction, probably via the PI3K/Akt/mTOR pathway, and inhibited tumor invasion and migration in vivo and in vitro. All above indicated that Brusatol is an encouraging anti-tumor drug candidate or a supplement to the current chemotherapeutic systematic plan.

Ye R ，Dai N ，He Q ，Guo P ，Xiang Y ，Zhang Q ，Hong Z ，Zhang Q ... -  《-》

Beclin 1-mediated autophagy in hepatocellular carcinoma cells: implication in anticancer efficiency of oroxylin A via inhibition of mTOR signaling.

Autophagy is a tightly-regulated catabolic process that involves the degradation of intracellular components via lysosomes. Although the pivotal role of autophagy in cell growth, development, and homeostasis has been well understood, its function in cancer prevention and intervention remains to be delineated. The aim of this study was to investigate the function and mechanism of autophagy induced by oroxylin A, a natural mono-flavonoid extracted from Scutellariae radix. We found for the first time that oroxylin A induced Beclin 1-mediated autophagy in human hepatocellular carcinoma HepG2 cells. Time-lapse video microscopy and western blotting studies showed that treatment of cells with 80 μM oroxylin A resulted in the conversion of water soluble MAP-LC3 (LC3-I) to the lipidated and autophagosome-associated form (LC3-II) after 12hours; then autophagosome-lysosome fusion and lysosome degradation after 24 hours was required in oroxylin A-mediated cell death. This induction was associated with the suppressing of PI3K-PTEN-Akt-mTOR signaling pathway by oroxylin A. Our results also showed that autophagy took place before noticeable apoptosis can be observed. It was further demonstrated that oroxylin A-triggered autophagy contributed to cell death using over-expression of autophagy-related gene (Atg5 and Atg7) and inhibition of autophagy by siBeclin 1 and 3-methyladenine (3-MA). In vivo study, oroxylin A inhibited xenograft tumor growth and induced obvious autophagy in tumors. Taken together, we conclude that oroxylin A exhibits autophagy-mediated antitumor activity in a dose and time-dependent manner in vivo and in vitro. These findings define and support a novel function of autophagy in promoting death of hepatocellular carcinoma cells.

Zou M ，Lu N ，Hu C ，Liu W ，Sun Y ，Wang X ，You Q ，Gu C ，Xi T ，Guo Q ... -  《-》

Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting HIF-1α via the PI3K/AKT/mTOR pathway.

Wang H ，Zhang C ，Xu L ，Zang K ，Ning Z ，Jiang F ，Chi H ，Zhu X ，Meng Z ... -  《Oncotarget》