Reinforcement of Sorafenib Anti-osteosarcoma Effect by Amentoflavone Is Associated With the Induction of Apoptosis and Inactivation of ERK/NF-κB.

BACKGROUND/AIM: Sorafenib has been reported to show anti-osteosarcoma (anti-OS) efficacy by inhibiting metastasis; however, a phase II trial suggested that further combination with other agents could be necessary to achieve permanent remission. Herein, we aimed to identify whether amentoflavone, an abundant natural bioflavonoid found in many medicinal plants, can improve the treatment efficacy of sorafenib in OS. MATERIALS AND METHODS: Cell viability, metastasis, apoptosis, and nuclear translocation of NF-κB after amentoflavone combined with sorafenib were assayed by MTT, transwell migration/invasion, western blotting, flow cytometry, and immunofluorescence staining, respectively. RESULTS: The sorafenib-induced cytotoxicity and apoptosis of U-2 OS was enhanced by combining treatment with QNZ (NF-κB inhibitor) or amentoflavone. NF-κB nuclear translocation, NF-κB phosphorylation, and metastasis capacity of U-2 OS cells were inhibited by amentoflavone combined with sorafenib. CONCLUSION: Amentoflavone may sensitize OS to sorafenib treatment by inducing intrinsic and extrinsic apoptosis and inhibiting ERK/NF-κB signaling transduction.

Magnolol Induces the Extrinsic/Intrinsic Apoptosis Pathways and Inhibits STAT3 Signaling-Mediated Invasion of Glioblastoma Cells.

Glioblastoma multiforme (GBM) is the most common form of malignant brain tumor, with poor prognosis; the efficacy of current standard therapy for GBM remains unsatisfactory. Magnolol, an herbal medicine from Magnolia officinalis, exhibited anticancer properties against many types of cancers. However, whether magnolol suppresses GBM progression as well as its underlying mechanism awaits further investigation. In this study, we used the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay, apoptosis marker analysis, transwell invasion and wound-healing assays to identify the effects of magnolol on GBM cells. We also validated the potential targets of magnolol on GBM with the GEPIA (Gene Expression Profiling Interactive Analysis) and Western blotting assay. Magnolol was found to trigger cytotoxicity and activate extrinsic/intrinsic apoptosis pathways in GBM cells. Both caspase-8 and caspase-9 were activated by magnolol. In addition, GEPIA data indicated the PKCδ (Protein kinase C delta)/STAT3 (Signal transducer and activator of transcription 3) signaling pathway as a potential target of GBM. Magnolol effectively suppressed the phosphorylation and nuclear translocation of STAT3 in GBM cells. Meanwhile, tumor invasion and migration ability and the associated genes, including MMP-9 (Matrix metalloproteinase-9) and uPA (Urokinase-type plasminogen activator), were all diminished by treatment with magnolol. Taken together, our results suggest that magnolol-induced anti-GBM effect may be associated with the inactivation of PKCδ/STAT3 signaling transduction.

Amentoflavone Induces Cell-cycle Arrest, Apoptosis, and Invasion Inhibition in Non-small Cell Lung Cancer Cells.

BACKGROUND/AIM: Amentoflavone, an effective compound derived from medicinal plants, has been shown to boost therapeutic efficacy of chemotherapy in non-small cell lung cancer (NSCLC). However, anti-NSCLC effect of amentoflavone is ambiguous. The major purpose of the present study was to verify the inhibitory effects of amentoflavone in NSCLC cells. MATERIALS AND METHODS: The effects of amentoflavone on growth and invasion of NSCLC CL-1-5-F4 cells were evaluated by cell viability assay, flow cytometry, colony formation assay, nuclear factor-kappa B (NF-κB) reporter gene assay, immunofluorescence staining, transwell invasion, and western blot assay. RESULTS: Amentoflavone effectively induced cell growth inhibition, G1 cell-cycle arrest, apoptosis, and suppression of invasion. Furthermore, amentoflavone not only triggered expression of p27, cleaved caspase-3, -8 also reduced NF-κB signaling, protein levels of matrix metalloproteinase (MMP)-2, -9, Cyclin-D1, and vascular endothelial growth factor (VEGF). CONCLUSION: Cell-cycle arrest, apoptosis induction, NF-κB signaling inhibition are associated with amentoflavone-inhibited growth and invasion of NSCLC cells.