Inhibition of glycolytic metabolism in glioblastoma cells by Pt3glc combinated with PI3K inhibitor via SIRT3-mediated mitochondrial and PI3K/Akt-MAPK pathway.

Glioblastoma multiforme (GBM) is the most malignant and aggressive glioma with abnormal expression of genes that mediate glycolytic metabolism and tumor cell growth. Petunidin-3-O-glucoside (Pt3glc) is a kind of anthocyanin in the red grape and derived beverages, representing the most common naturally occurring anthocyanins with a reduced incidence of cancer and heart diseases. In this study, whether Pt3glc could effectively regulate glycolysis to inhibit GBM cell was investigated by using the DBTRG-05MG cell lines. Notably, Pt3glc displayed potent antiproliferative activity and significantly changed the protein levels related to both glycolytic metabolism and GBM cell survival. The expression of the proapoptotic protein Bcl-2-associated X protein was increased with concomitant reduction on the levels of the antiapoptotic protein B-cell lymphoma 2 and caspase-3 activity. Furthermore, the levels of survival signaling proteins, such as protein kinase B (Akt) and phospho-Akt (Scr473), extracellular signal-regulated kinase (ERK) and phospho-ERK, were significantly decreased by Pt3glc in combination with the phosphoinositide 3-kinase (PI3K) inhibitor of LY294002. Most importantly, the levels of Sirtuin 3 (SIRT3) and phosphorylated p53 were also downregulated, indicating that Pt3glc combinated with PI3K inhibitor could induce GBM cell death may act via the SIRT3/p53-mediated mitochondrial and PI3K/Akt-ERK pathways. Our findings thus provide rational evidence that the combination of Pt3glc with PI3K inhibitor, which target alternative pathways in GBM cells, may be a useful adjuvant therapy in glioblastoma treatment.

The role of Myc and let-7a in glioblastoma, glucose metabolism and response to therapy.

Glioblastoma multiforme (GBM) is thought to result from an imbalance between glucose metabolism and tumor growth. The Myc oncogene and lethal-7a microRNA (let-7a miRNA) have been suggested to cooperatively regulate multiple downstream targets leading to changes in chromosome stability, gene mutations, and/or modulation of tumor growth. Here, we review the roles of Myc and let-7a in glucose metabolism and tumor growth and addresses their future potential as prognostic markers and therapeutic tools in GBM. We focus on the functions of Myc and let-7a in glucose uptake, tumor survival, proliferation, and mobility of glioma cells. In addition, we discuss how regulation of different pathways by Myc or let-7a may be useful for future GBM therapies. A large body of evidence suggests that targeting Myc and let-7a may provide a selective mechanism for the deregulation of glucose metabolic pathways in glioma cells. Indeed, Myc and let-7a are aberrantly expressed in GBM and have been linked to the regulation of cell growth and glucose metabolism in GBM. This article is part of a Special Issue entitled "Targeting alternative glucose metabolism and regulate pathways in GBM cells for future glioblastoma therapies".

The phosphatidylinositol 3-kinase/Akt and c-Jun N-terminal kinase signaling in cancer: Alliance or contradiction? (Review).

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and c-Jun N-terminal kinase (JNK) pathway are responsible for regulating a variety of cellular processes including cell growth, migration, invasion and apoptosis. These two pathways are essential to the development and progression of tumors. The dual roles of JNK signaling in apoptosis and tumor development determine the different interactions between the PI3K/Akt and JNK pathways. Activation of PI3K/Akt signaling can inhibit stress- and cytokine-induced JNK activation through Akt antagonizing and the formation of the JIP1-JNK module, as well as the activities of upstream kinases ASK1, MKK4/7 and MLK. On the other hand, hyperactivation of Akt and JNK is also found in cancers that harbor EGFR overexpression or loss of PTEN. Understanding the activation mechanism of PI3K/Akt and JNK pathways, as well as the interplays between these two pathways in cancer may contribute to the identification of novel therapeutic targets. In the present report, we summarized the current understanding of the PI3K/Akt and JNK signaling networks, as well as their biological roles in cancers. In addition, the interactions and regulatory network between PI3K/Akt and JNK pathways in cancer were discussed.

Advances in lipid-based drug delivery: enhancing efficiency for hydrophobic drugs.

INTRODUCTION: Many drug candidates with high therapeutic efficacy have low water solubility, which limits the administration and transport across physiological barriers, for example, the tumor tissue barrier. Therefore, strategies are needed to permeabilize the physiological barriers safely so that hydrophobic drugs may be delivered efficiently. AREAS COVERED: This review focuses on prospects for therapeutic application of lipid-based drug delivery carriers that increase hydrophobic drugs to improve their solubility, bioavailability, drug release, targeting and absorption. Moreover, novel techniques to prepare for lipid-based drug delivery to extend pharmaceuticals with poor bioavailability such as surface modifications of lipid-based drug delivery are presented. Industrial developments of several drug candidates employing these strategies are discussed, as well as applications and clinical trials. EXPERT OPINION: Overall, hydrophobic drugs can be encapsulated in the lipid-based drug delivery systems, represent a relatively safe and promising strategy to extend drug retention, lengthen the lifetime in the circulation, and allow active targeting to specific tissues and controllable drug release in the desirable sites. However, there are still noticeable gaps that need to be filled before the theoretical advantage of these formulations may truly be realized such as investigation on the use of lipid-based drug delivery for administration routes. This research may provide further interest within the area of lipid-based systems, both in industry and in the clinic.

The catalytic phosphoinositol 3-kinase isoform p110δ is required for glioma cell migration and invasion.

Glioblastoma multiforme (GBM) is a highly invasive and aggressive primary brain tumour in which loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a negative regulator of PI3K signalling, is a common feature. PTEN/PI3K/Akt signalling is involved in the regulation of proliferation, apoptosis and cell migration. Deregulation of PI3K signalling is considered an essential driver in gliomagenesis. However, the role of different PI3K isoforms in glioma is still largely unclear. Here we show that the catalytic PI3K isoform p110δ is consistently expressed at a high level in various glioma cell lines. We used small interfering RNA to selectively deplete p110δ and to determine its tumourigenic roles in PTEN-deficient cells. Interestingly, knockdown of p110δ decreased the cell migration and invasion ability of all GBM cell lines tested. Mechanistically, p110δ knockdown reduced the protein levels of focal adhesion kinase and cell division cycle 42, key regulators of cellular migration. In contrast, pharmacologic inhibition of p110δ by IC87114 or CAL-101 also clearly impaired glioma cell migration but had no obvious effect on the invasion capacity thus pinpointing to possible kinase-dependent and -independent roles of p110δ in glioma pathology. In summary, our data provide novel evidence that in glioma cells p110δ is a key regulator of cell movement and thus may contribute to the highly invasive phenotype of GBM. Isoform specific targeting of PI3Kδ may be beneficial in the treatment of glioblastoma multiforme by specifically inhibiting tumour cell migration capacity.