Lycorine hydrochloride interferes with energy metabolism to inhibit chemoresistant glioblastoma multiforme cell growth through suppressing PDK3.

Glioblastoma multiforme (GBM) is the highest grade of glioma. Tumours, including GBM, possess reprogrammed metabolism, such as altered aerobic glycolysis and aberrant energy production. Lycorine hydrochloride (LH) was extracted from the bulb of Lycoris radiata. The previous study indicated that LH exerts antiviral, anti-inflammatory and antitumour effects. However, the effect of LH on GBM and the underlying molecular mechanism remain unclear. Our study revealed that LH restrained chemoresistant GBM cells growth by inhibiting PDK3 expression in vitro and in vivo. Functionally, LH inhibited the proliferation and invasive capacity of chemoresistant GBM cells in dose-dependent manner. Metabolomics and cellular energy analyses showed that LH decreased extracellular acidification rates while increased oxidative respiration and ROS levels. Mechanistically, LH inhibits the growth of GBM chemoresistant cells by regulating the expression of apoptosis-related proteins, while overexpression of of PDK3 can reverse the antitumor effect of LH. In conclusion, our study revealed that LH could reprogramme cell energy metabolism, including aerobic glycolysis suppression and oxidative phosphorylation hyperactivation by inhibiting PDK3. PDK3 may be a candidate therapeutic target for chemoresistant GBM treatment with LH.

Recent progress of hydrogel-based local drug delivery systems for postoperative radiotherapy.

Surgical resection and postoperative radiotherapy remained the most common therapeutic modalities for malignant tumors. However, tumor recurrence after receiving such combination is difficult to be avoided because of high invasiveness and radiation resistance of cancer cells during long-term therapy. Hydrogels, as novel local drug delivery systems, presented excellent biocompatibility, high drug loading capacity and sustained drug release property. Compared with conventional drug formulations, hydrogels are able to be administered intraoperatively and directly release the entrapped therapeutic agents to the unresectable tumor sites. Therefore, hydrogel-based local drug delivery systems have their unique advantages especially in sensitizing postoperative radiotherapy. In this context, classification and biological properties of hydrogels were firstly introduced. Then, recent progress and application of hydrogels for postoperative radiotherapy were summarized. Finally, the prospects and challenges of hydrogels in postoperative radiotherapy were discussed.

The value of texture analysis in peritumoral edema of differentiating diagnosis between glioblastoma and primary brain lymphoma.

OBJECTIVE: To evaluate the value of texture analysis of routine MRI image in peritumoral edema of differentiating diagnosis between glioblastoma (GBM) and primary brain lymphoma (PBL). METHODS: The MRI imaging data of 22 patients with glioblastoma and 21 patients with PBL who were hospitalized in our hospital from January 2010 to October 2018 were selected. All the patients were pathologically diagnosed as glioblastoma or PBL, and MRI plain scan and enhanced examination were performed before operation. FireVoxel software was used to delineate the region of interest (ROI) on the most obvious level of peritumoral edema based on T1WI enhancement. Texture parameters were extracted and compared between glioblastoma and PBL. RESULTS: In the glioblastoma group, the inhomogeneity, kurtosis and entropy texture parameters were statistically different from those in the PBL group. The entropy parameter area under the curve (AUC) (0.903) was significantly better than the kurtosis parameter AUC (0.859) and the inhomogeneity parameter AUC (0.729). When the entropy parameter Cut-off point = 3.883, the sensitivity, specificity and accuracy of glioblastoma and PBL were 85.7, 86.4 and 86.0%, respectively, by differential diagnosis. CONCLUSION: Texture analysis of tumor peritumoral edema provided quantifiable information, which might be a new method for differentiating glioblastoma from PBL.

Chrysophanol Induced Glioma Cells Apoptosis via Activation of Mitochondrial Apoptosis Pathway.

Glioma is a common intracranial tumor originated from neuroglia cell. Chrysophanol is an anthraquinone derivative proved to exert anticancer effects in various cancers. This paper investigated the effect and mechanism of chrysophanol in glioma. Glioma cell lines U251 and SHG-44 were adopted in the experiments. The cells were treated with chrysophanol at different concentrations (0, 10, 20 50, 100 and 200 µM) for 48 h in the study, and then processed with MitoTempo. Mitochondria and cytosol were isolated to investigate the role of mitochondria during chrysophanol functioning on glioma cells. Cell viability was detected through 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide (MTT) assay, and cell apoptosis, cell cycle as well as relative reactive oxygen species (ROS) were assessed by flow cytometry. Expressions of Cytosol Cyt C, cleaved caspase-3, cleaved caspase-9, Cyclin D1 and Cyclin E were evaluated by western blot. In U251 and SHG-44 cells, with chrysophanol concentration rising, cell viability, expressions of Cyclin D1 and Cyclin E were decreased while cell apoptosis, levels of cleaved caspase-3, cleaved caspase-9 and Cytosol Cyt C as well as ROS accumulation were increased with cell cycle arrested in G1 phase. Besides, chrysophanol promoted ROS accumulation, cell apoptosis and transfer of Cyt C from mitochondria to cytosol in cells while MitoTempo partly reversed the effect of chrysophanol. Chrysophanol promoted cell apoptosis via activating mitochondrial apoptosis pathway in glioma.

Correction to: Co-delivery of GOLPH3 siRNA and gefitinib by cationic lipid-PLGA nanoparticles improves EGFR-targeted therapy for glioma.

The correct affiliation no 2 is presented in this paper.

Co-delivery of GOLPH3 siRNA and gefitinib by cationic lipid-PLGA nanoparticles improves EGFR-targeted therapy for glioma.

Glioblastoma is one of the most aggressive types of brain tumor. Epidermal growth factor receptors (EGFRs) are overexpressed in glioma, and EGFR amplifications and mutations lead to rapid proliferation and invasion. EGFR-targeted therapy might be an effective treatment for glioma. Gefitinib (Ge) is an EGFR tyrosine kinase inhibitor (TKI), and Golgi phosphoprotein 3 (GOLPH3) expression is associated with worse glioma prognosis. Downregulation of GOLPH3 could promote EGFR degradation. Here, an angiopep-2 (A2)-modified cationic lipid-poly (lactic-co-glycolic acid) (PLGA) nanoparticle (A2-N) was developed that can release Ge and GOLPH3 siRNA (siGOLPH3) upon entering glioma cells and therefore acts as a combinatorial anti-tumor therapy. The in vitro and in vivo studies proved that A2-N/Ge/siGOLPH3 successfully crossed the blood-brain barrier (BBB) and targeted glioma. Released siGOLPH3 effectively silenced GOLPH3 mRNA expression and further promoted EGFR and p-EGFR degradation. Released Ge also markedly inhibited EGFR signaling. This combined EGFR-targeted action achieved remarkable anti-glioma effects and could be a safe and effective treatment for glioma. KEY MESSAGES: Angiopep-2-modified cationic lipid polymer can penetrate the BBB. Gefitinib can inhibit EGFR signaling and block the autophosphorylation of critical tyrosine residues on EGFR. GOLPH3 siRNA can be transfected into glioma and downregulate GLOPH3 expression. A2-N/Ge/siGOLPH3 can inhibit glioma growth.

Angiopep-2 Modified Cationic Lipid-Poly-Lactic-Co-Glycolic Acid Delivery Temozolomide and DNA Repair Inhibitor Dbait to Achieve Synergetic Chemo-Radiotherapy Against Glioma.

The therapeutic treatment of glioblastoma multiforme (GBM) remains a major challenge. Synergistic chemotherapy and radiotherapy (RT) have been considered the standard clinical therapy for malignant glioma, but there are some outstanding problems. First, gliomas are deemed exceedingly radio-resistant tumors, owing to efficient DNA double-strand break repair. In addition, the first-line chemotherapeutic agent (temozolomide, TMZ) for glioma shows extensive side effects and low accumulation in brain tumors. Therefore, we designed and constructed an Angiopep-2 modified cationic lipid-Poly-lactic-co-glycolic acid (PLGA), Angiopep-2 (A2)/DSPE-PEG2000/DOTAP/PLGA (APDP), to transport TMZ and a DNA repair inhibitor (Dbait) into glioblastoma cells, achieving concomitant chemo-radiotherapy treatment of glioma. At the cellular level, the APDP+TMZ/Dbait can be well endocytosed and enhance accumulation of the agent in brain tumors. Furthermore, the nanoparticle combined with Dbait improves the efficiency of radiotherapy in GBM. Our experimental data demonstrate that APDP+TMZ/Dbait has great potential as a multipurpose nanomedicine for the synergistic chemo-radiotherapy and radio-sensitization of malignant glioma in precise medical applications.

Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth.

PURPOSE: Glioma is a highly aggressive and lethal brain tumor. Signal transducers and activators of transcription (STAT) pathway are widely implicated in glioma carcinogenesis. Our previous study found that the Fynrelated kinase (FRK) gene, plays as a tumor suppressor in the development and progression of glioma. This study aimed to investigate the role of FRK in the activation pathway of STATs and its effect on the growth of glioma. METHODS: The U251 and U87 cells with stable FRK overexpression were generated by lentivirus technique. The effects of FRK on the related proteins of STAT signaling pathway were detected by western blotting. Coimmunoprecipitation was used to detect the association of FRK and STAT1. The effects of STAT1 on the proliferation of glioma cells were detected by CCK8 or Edu cell proliferation assays. The expressions and correlation of FRK and p-STAT1 in glioma tissues were detectd by western blotting or immunohistochemistry. The effect of FRK on the growth of glioma was investigated in vivo mouse model. RESULTS: The level of p-JAK2 and p-STAT1 increased after FRK overexpression, while they decreased after FRK downregulation both in U251 and U87 cells. However, FRK had no effect on STAT3 phosphorylation. FRK-induced STAT1 activation was not dependent on JAK2. FRK associated with STAT1, induced STAT1 nuclear translocation and regulated the expressions of STAT1-related target genes. STAT1 overexpression suppressed the proliferation of glioma cells. In contrast, STAT1 knockdown by siRNA promoted glioma cell growth. Importantly, down-regulation of STAT1 partially attenuated FRK-induced growth suppression. The clinical sample-based study indicated that the expression of FRK was significantly correlated with the expression of p-STAT1. FRK significantly inhibited glioma tumor growth in vivo. CONCLUSIONS: Our findings highlighted a critical role of FRK in tumor suppression ability through promoting STAT1 activation, and provided a potential therapeutic target for glioma.

Self-assembled angiopep-2 modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles delivery TMZ for glioma synergistic TMZ and RT therapy.

The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GBM). However, TMZ + RT causes excess toxicity in patients. In this study, we prepared angiopep-2 (A2) modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles for TMZ delivery (A2-P(MIs)25/TMZ) to achieve synergistic effects against glioma. This A2-P(MIs)25/TMZ display highly promising advantages: (1) a hydrophobic P-(MIs)25 core where poorly water-soluble TMZ can be encapsulated; (2) nitro groups of the hydrophobic P-(MIs)25 core that are converted into hydrophilic amino groups (P(NH2s)25) under low oxygen conditions to mimic the oxygen-increased sensitization to RT; (3) a lipid monolayer at the interface of the core and the shell to modify the A2 (a specific ligand for low-density lipoprotein receptor-related protein-1 (LRP-1), which are expressed in the blood-brain barrier (BBB) and human glioma cells), thereby enhancing the drug encapsulation efficiency in glioma. These nanoparticles appear as a promising and robust nanoplatforms for TMZ and hypoxic cell radiosensitization delivery.

Delivery of Doxorubicin from Hyaluronic Acid-Modified Glutathione-Responsive Ferrocene Micelles for Combination Cancer Therapy.

A combination of different chemotherapy approaches can obtain the best response for many cancers. However, the greatest challenge is the development of a nanoparticle formulation that can encapsulate different chemotherapeutic agents to achieve the proper synergetic chemotherapy for the tumor. Here, amphiphilic ferrocenium-tetradecyl (Fe-C14) was constructed to form cationic micelles in an aqueous solution via self-assembly. Then, it was coated by hyaluronic acid (HA) through electrostatic interactions to generate HA-Fe-C14 micelles. The HA-Fe-C14 micelles were used to deliver doxorubicin (DOX), and it showed that the DOX could be released rapidly under a high-GSH tumor environment. The HA-Fe-C14/DOX micelles were able to accumulate efficiently in tumor and showed significant anticancer effect both in vitro and in vivo. These results suggest that HA-Fe-C14/DOX micelles are a useful drug delivery system that enhances synergic antitumor treatment effects.

Inhibition of glioma growth by a GOLPH3 siRNA-loaded cationic liposomes.

PURPOSE: GOLPH3 has been shown to be involved in glioma proliferation. In this study, we aimed to demonstrate that GOLPH3 can serve as a target for glioma gene therapy. METHODS: During the experiment, cationic liposomes with angiopep-2 (A2-CL) were used to deliver siGOLPH3 crossing the blood-brain barrier and reaching the glioma. RESULTS: At the cellular level, the A2-CL/siGOLPH3 could silence GOLPH3 and then effectively inhibited the proliferation of cells. In vivo experiments, using U87-GFP-Luci-bearing BALB/c mouse models, we demonstrated that A2-CL could deliver GOLPH3-siRNA specifically to glioma and effectively inhibit glioma growth. CONCLUSIONS: This study shows that GOLPH3 has great potential as a target for the gene therapy of glioma and is of great value in precise medical applications.