Wogonin induces cross-regulation between autophagy and apoptosis via a variety of Akt pathway in human nasopharyngeal carcinoma cells.

Autophagy as well as apoptosis is an emerging target for cancer therapy. Wogonin, a flavonoid compound derived from the traditional Chinese medicine of Huang-Qin, has anticancer activity in many cancer cells including human nasopharyngeal carcinoma (NPC). However, the involvement of autophagy in the wogonin-induced apoptosis of NPC cells was still uninvestigated. In this study, we found wogonin-induced autophagy had interference on the process of apoptosis. Wogonin-induced autophagy formation evidenced by LC3 I/II cleavage, acridine orange (AO)-stained vacuoles and the autophagosome/autolysosome images of TEM analysis. Activation of autophagy with rapamycin resulted in increased wogonin-mediated autophagy via inhibition of mTOR/P70S6K pathway. The functional relevance of autophagy in the antitumor activity was investigated by annexin V-positive stained cells and PARP cleavage. Induction of autophagy by rapamycin ameliorated the wogonin-mediated apoptosis, whereas inhibition of autophagy by 3-methyladenine (3-MA) or bafilomycin A1 increased the apoptotic effect. Interestingly, this study also found, in addition the mTOR/P70S6K pathway, wogonin also inhibited Raf/ERK pathway, a variety of Akt pathways. Inactivation of PI(3) K/Akt by their inhibitors significantly induced apoptosis and markedly sensitized the NPC cells to wogonin-induced apoptosis. This anticancer effect of Akt was further confirmed by SH6, a specific inhibitor of Akt. Importantly, inactivation of its downstream molecule ERK by PD98059, a MEK inhibitor, also induced apoptosis. This study indicated wogonin-induced both autophagy and apoptosis through a variety of Akt pathways and suggested modulation of autophagy might provide profoundly the potential therapeutic effect.

Chow SE ，Chen YW ，Liang CA ，Huang YK ，Wang JS ... -  《-》

Wogonin induces apoptosis and down-regulates survivin in human breast cancer MCF-7 cells by modulating PI3K-AKT pathway.

Wogonin, one of flavonoid compounds isolated from Chinese herbal plants Scutellaria baicalensis Georgi, has been recognized as a potent anti-cancer agent acting through control of growth, differentiation and apoptosis. However, the underlying molecular mechanism of its anti-cancer activity remains to be further elucidated. In this study, we investigated the potential role of wogonin in the induced-apoptosis of human breast cancer cells MCF-7. Wogonin was found to inhibit the proliferation of MCF-7 in a concentration and time-dependent manner, notably wogonin could induce G1 phase arrest of MCF-7 cells. Wogonin-induced apoptosis was accompanied by a significant decrease of the Bcl-2 and survivin and increase of Bax and p53. Wogonin also increased active apoptosis forms of caspases-3, -8, -9 significantly. Z-DEVD-fmk, a specific caspase-3 inhibitor, significantly inhibited wogonin-induced cell apoptosis. Wogonin also suppressed the phosphorylation of PI3K/Akt and induced phosphorylation of ERK. PD98059, a specific ERK inhibitor, significantly blocked wogonin-induced apoptosis. On the other hand, LY294002, a specific PI3K inhibitor, significantly increased wogonin-induced cell apoptosis. Further study indicated that LY294002 not only down-regulated the expression of survivin alone, but also enhanced the inhibition of survivin expression combined with wogonin. In conclusion, the pro-apoptotic effect of wogonin is mediated through the activation of ERK and the activation of caspases, and is correlated with the block of the PI3K/Akt/survivin signal pathways in MCF-7 cells.

Huang KF ，Zhang GD ，Huang YQ ，Diao Y ... -  《-》

Inhibition of Autophagy Potentiated the Antitumor Effect of Nedaplatin in Cisplatin-Resistant Nasopharyngeal Carcinoma Cells.

Liu Z ，Liu J ，Li L ，Nie D ，Tao Q ，Wu J ，Fan J ，Lin C ，Zhao S ，Ju D ... -  《-》

Inhibition of autophagy enhances apoptosis induced by the PI3K/AKT/mTor inhibitor NVP-BEZ235 in renal cell carcinoma cells.

The PI3K/AKT/mTOR pathway plays a key role in the development of the hypervascular tumor renal cell carcinoma (RCC). NVP-BEZ235 (NVP), a novel dual PI3K/mTOR inhibitor, showed great antitumor benefit and provided a treatment strategy in RCC. In this study, we test the effect of NVP on survival rate, apoptosis and autophagy in the RCC cell line, 786-0. We also explore the hypothesis that NVP, in combination with autophagy inhibitors, leads to apoptosis enhancement in 786-0 cells. The results showed that the PI3K/AKT/mTOR pathway proteins p-AKT and p-P70S6K were highly expressed in RCC tissue. We also showed that NVP inhibited cell growth and induced apoptosis and autophagy in RCC cells. The combination treatment of NVP with autophagy inhibitors enhanced the effect of NVP on suppressing 786-0 growth and induction of apoptosis. This study proposes a novel treatment paradigm where combining PI3K/AKT/mTOR pathway inhibitors and autophagy inhibitors lead to enhanced RCC cell apoptosis.

Li H ，Jin X ，Zhang Z ，Xing Y ，Kong X ... -  《-》

Inhibition of Autophagy Promotes Salinomycin-Induced Apoptosis via Reactive Oxygen Species-Mediated PI3K/AKT/mTOR and ERK/p38 MAPK-Dependent Signaling in Human Prostate Cancer Cells.

Kim KY ，Park KI ，Kim SH ，Yu SN ，Park SG ，Kim YW ，Seo YK ，Ma JY ，Ahn SC ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》