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Glioma is among the most common human malignancies with poor prognosis. Glioma stem cells (GSCs) are the culprit of glioma, suggesting that GSCs are potential therapeutic targets. Notch signaling pathway plays a pivotal role for the function of GSCs, implying that suppression of Notch pathway may be an effective strategy for GSC-targeting therapy. In this study, we found that alpinetin, a natural compound, can suppress the proliferation and invasiveness of GSCs and induce apoptosis in GSCs. Immunoblot analysis and luciferase assay revealed that Notch signaling was suppressed by alpinetin. Furthermore, restoration of Notch signaling activity rescued the effect of alpinetin on GSC's function. The anti-tumor activity of alpinetin was further confirmed in an animal model. Collectively, targeting of GSC by alpinetin is an effective strategy for glioma therapy.

Purpose: Aplysin, a natural brominate compound from marine organisms, has been demonstrated to exhibit anti-tumor activity, mainly by inducing apoptosis and cell cycle arrest. However, its effect on glioma is still unknown. In this study, we evaluated the effects of aplysin on the malignant properties of glioma cells and its enhancing effect on temozolomide (TMZ) action against drug-resistant glioma cell lines., Methods: We employed several human glioma cell lines and primary glioma cells to address this issue with multidisciplinary approaches., Results: The combined application of aplysin and TMZ significantly sensitizes glioma cells to TMZ action, compared with TMZ alone. miRNA profile analysis revealed that the abundance of miR-181, an important glioma tumor suppressors believed to enhance TMZ effect, was greatly elevated in aplysin-treated glioma cell lines. The aplysin-induced TMZ sensitivity is dependent on MEK1 in glioma cells. Overexpression of MEK1 was able to abolish the effect of aplysin on glioma cells., Conclusions: We found that aplysin can enhance the effect of TMZ on glioma cells by increasing miR-181 expression.

Adenovirus-mediated virotherapy is one of the promising therapeutic approaches for glioma treatment. However, its replication efficiency and specificity still failed to meet the requirements for clinical treatment. To improve the anti-tumor activity and specificity of oncolytic adenoviruses (OA), we applied multiple miRNA response elements (MREs) of miR-124, miR-128, miR-146b and miR-218, whose expressions were downregulated in glioma cells, to enable OA to be specific to glioma. Adenoviral E1A protein regulated by these 4 MREs (OA-4MREs) was shown to be highly expressed in glioma cells, but not in normal cells. The selective E1A expression led to glioma-specific replication and cytotoxicity of OA-4MREs. Animal experiments also showed that OA-4MREs exhibited improved anti-tumor activities for both subcutaneous and intracranial glioma xenografts, without significant toxicity to normal brain and liver tissues. Collectively, we demonstrated that oncolytic adenovirus, whose replication was regulated by MREs, may be promising biological agents for glioma treatment., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: MicroRNAs (miRNAs) are short, non-coding RNAs that regulate the expression of multiple target genes. Deregulation of miRNAs is common in human tumorigenesis. Low level expression of miR-26b has been found in glioma cells. However, its underlying mechanism of action has not been determined., Methodology/principal Findings: Real-time PCR was employed to measure the expression level of miR-26b in glioma patients and cells. The level of miR-26b was inversely correlated with the grade of glioma. Ectopic expression of miR-26b inhibited the proliferation, migration and invasion of human glioma cells. A binding site for miR-26b was identified in the 3'UTR of EphA2. Over-expression of miR-26b in glioma cells repressed the endogenous level of EphA2 protein. Vasculogenic mimicry (VM) experiments were performed to further confirm the effects of miR-26b on the regulation of EphA2, and the results showed that miR-26b inhibited the VM processes which regulated by EphA2., Significance: This study demonstrated that miR-26b may act as a tumor suppressor in glioma and it directly regulates EphA2 expression. EphA2 is a direct target of miR-26b, and the down-regulation of EphA2 mediated by miR-26b is dependent on the binding of miR-26b to a specific response element of microRNA in the 3'UTR region of EphA2 mRNA.

The programmed cell death 4 (PDCD4) tumor-suppressor gene regulates cell apoptosis, protein translation, signal transduction, and induction of mediators of inflammation. However, the mechanism by which PDCD4 is down-regulated and regulates tumor growth remains elusive. In this study, we showed that PDCD4 is down-regulated in glioma cells and acts as a tumor suppressor. Based on the TCGA data, we confirmed that AKT2, but not AKT1 or AKT3, interacts with PDCD4, thus leading to the suppression of PDCD4 in glioma cells. Moreover, the analysis suggested that PDCD4 regulates the expression of IL-5, CCL-5, VEGF, and CXCL10 via the NF-kB pathway. Additionally, depletion of levels of PDCD4 promoted angiogenic activity of glioma cells via the VEGF-STAT3 pathway. When tumor cells over-expressing PDCD4 were injected into nude mice, the increased expression of PDCD4 blocked tumorigenesis and prolonged overall survival. Our study indicates the need to develop drugs that can modulate the expression of PDCD4 and test their efficacy in clinical trials.

Mitogen-activated protein kinases/Extracellular signal-regulated kinase (MAPK/ERK) pathway is essential for migration and invasion of malignant glioma. It is efficient to inhibit migration and invasion of glioma cells by targeting this pathway. Oleanolic acid (OA) has been well demonstrated to suppress survival, growth and angiogenesis of glioma cells. However, it is still unknown if OA affects the migration and invasion of glioma cells. We utilized U-87 MG glioma cell lines and primary glioma cells from patients to study the effect of OA on migration and invasion of glioma cells with multidisciplinary approaches. In this study, we found that OA significantly decreased the ability of glioma cells to migrate and invade. Epithelial-mesenchymal transition (EMT) of glioma cells was also suppressed by OA treatment. Furthermore, MAPK/ERK pathway was greatly inhibited in glioma cells under OA treatment. MAPK/ERK reactivation induced by a recombinant lentiviral vector, Lv-MEK, was able to rescue the inhibitory effect of OA on migration and invasion of glioma cells. Taken together, we provided evidences that OA was a MAPK/ERK pathway-targeting anti-tumor agent. Although the concentrations we used exceeded its physiological level, OA may be used to prevent migration and invasion of glioma cells by developing its derivatives with enhanced bioactivity. [ABSTRACT FROM AUTHOR]