Bufalin inhibits ovarian carcinoma via targeting mTOR/HIF-α pathway.

Ovarian cancer is a severe health threat for women with increased incidence and stymied development in diagnosis and therapy. Drug resistance is still a big challenge. Bufalin is a multi-functional steroid-like compound extracted from natural product Chansu and has been tested as antitumour agent recently. The application and mechanism of bufalin in ovarian cancer remain unclear yet. Bufalin was first examined in ovarian epithelial cancer cell as well as primary ovarian tissue to evaluate its inhibitory activity in cell growth and migration, followed by the validation in xenograft tumour model and the patient samples. Bufalin is well tolerated by normal ovarian tissue at up to 40 μM and suppresses the cell growth and migration at 10 μM and xenograft tumour growth at 0.1mg/kg dosage. Bufalin inhibits the mammalian target of rapamycin (mTOR) activation and subsequently decreases hypoxia-induced factor 1 alpha (HIF-1α) level. Overexpression of HIF-1α could abolish the pro-apoptotic and antimigration activity of bufalin in cell culture. Strikingly, low HIF-1α level was correlated with improved responsiveness to cisplatin treatment in ovarian cancer patients. Bufalin was a potent inhibitor of cell growth and migration in ovarian cancer cells through suppression of mTOR activation and HIF-1α induction. Bufalin could be used to enhance the efficacy of cisplatin in ovarian cancer patients.

Su S ，Dou H ，Wang Z ，Zhang 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》

Knockdown of Hypoxia-Inducible Factor 1α (HIF-1α) Promotes Autophagy and Inhibits Phosphatidylinositol 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Signaling Pathway in Ovarian Cancer Cells.

Huang J ，Gao L ，Li B ，Liu C ，Hong S ，Min J ，Hong L ... -  《MEDICAL SCIENCE MONITOR》

Ivermectin Augments the In Vitro and In Vivo Efficacy of Cisplatin in Epithelial Ovarian Cancer by Suppressing Akt/mTOR Signaling.

The poor outcomes in epithelial ovarian cancer necessitate new treatments. In this work, we systematically analyzed the inhibitory effects of ivermectin and the molecular mechanism of its action in ovarian cancer. The effects of ivermectin alone and its combination with cisplatin on growth and survival were examined using cultured ovarian cancer cells and a xenograft mouse model. The molecular mechanism of action of ivermectin, focusing on Akt/mTOR signaling, was elucidated. Ivermectin arrested growth in the G2/M phase and induced caspase-dependent apoptosis in ovarian cancer, regardless of specific cellular and molecular differences. Ivermectin significantly augmented the inhibitory effect of cisplatin on ovarian cancer cells in a dose-dependent manner. Mechanistically, ivermectin suppressed the phosphorylation of key molecules in the Akt/mTOR signaling pathway in ovarian cancer cells. In addition, overexpression of constitutively active Akt restored ivermectin-induced inhibition of Akt/mTOR, growth arrest and apoptosis. In an ovarian cancer xenograft mouse model, ivermectin alone significantly inhibited tumor growth. In combination with cisplatin, tumor growth was completely reversed over the entire duration of drug treatment without any toxicity. Furthermore, the concentrations of ivermectin used in our study are pharmacologically achievable. Our work suggests that ivermectin may be a useful addition to the treatment armamentarium for ovarian cancer and that targeting Akt/mTOR signaling is a therapeutic strategy to increase chemosensitivity in ovarian cancer.

Zhang X ，Qin T ，Zhu Z ，Hong F ，Xu Y ，Zhang X ，Xu X ，Ma A ... -  《-》

MiR-497 decreases cisplatin resistance in ovarian cancer cells by targeting mTOR/P70S6K1.

Xu S ，Fu GB ，Tao Z ，OuYang J ，Kong F ，Jiang BH ，Wan X ，Chen K ... -  《Oncotarget》