Solitary Sclerotic Fibroma of Right Cerebellopontine Angle.

Sclerotic fibroma (storiform collagenoma) is a fibrotic tumor that occurs mainly in patients with Cowden syndrome, but it can also occur in isolation, as detailed in previous reports. Here we present a case of a solitary sclerotic fibroma in cerebellopontine angle. Brain magnetic resonance imaging revealed a lesion showing hypointense signal on both T1 and T2. The lesion was not enhanced after administering gadolinium. The tumor was removed integrally by surgery.

Knockdown of NUSAP1 inhibits cell proliferation and invasion through downregulation of TOP2A in human glioblastoma.

Nucleolar and spindle associated protein 1 (NUSAP1), an indispensable mitotic regulator, has been reported to be involved in the development, progression, and metastasis of several types of cancer. Here, we investigated the expression and biological function of NUSAP1 in human glioblastoma (GBM), an aggressive brain tumor type with largely ineffective treatment options. Analysis of the molecular data in CGGA, TCGA and Rembrandt datasets demonstrated that NUSAP1 was significantly upregulated in GBM relative to low grade gliomas and non-neoplastic brain tissue samples. Kaplan-Meier analysis indicated that patients with tumors showing high NUSAP1 expression exhibited significantly poorer survival in both CGGA (P = 0.002) and Rembrandt cohorts (P = 0.017). Analysis of RNA sequencing data from P3-cells with stable knockdown of NUSAP1 revealed topoisomerase 2A (TOP2A) as a possible molecule downregulated by the loss of NUSAP1. Molecular analysis of the CGGA data revealed a strong correlation between NUSAP1 and TOP2A expression in primary gliomas and recurrent gliomas samples. SiRNA knockdown of either NUSAP1 or TOP2A in U251, T98 and GBM derived patient P3 cells inhibited GBM cell proliferation and invasion, and induced cell apoptosis. Finally, stable knockdown of NUSAP1 with shRNA led to decreased tumor growth in an orthotopic xenograft model of GBM in mice. Taken together, NUSAP1 gene silencing induced apoptosis possibly through the downregulation of the candidate downstream molecule TOP2A. Interference with the expression of NUSAP1 might therefore inhibit malignant progression in GBM, and NUSAP1 might thus serve as a promising molecular target for GBM treatment.

Primary Intradural Hemangioendothelioma of Lumbar Spine.

Hemangioendotheliomas are rare, intermediate-grade malignant tumors in the neuraxis, mainly involving the brain and meninges. Hemangioendotheliomas of the spine have been encountered more often in the vertebral body than the intradural space. Here, we present a rare case of a unique intradural hemangioendothelioma of the lumbar spine; only a few such cases exist in the literature.

Deployment of a bioabsorbable plate as the rigid buttress for skull base repair after endoscopic pituitary surgery.

BACKGROUND: Bioresorbable alloplastic implants have become desirable as a rigid buttress for reconstructing skull base defects. This study aimed to describe the use of a biodegradable plate (PolyMax RAPID) in skull base repair of endoscopic endonasal pituitary surgery and to investigate the clinical outcome and safety of this novel method. METHODS: Between January 2019 and January 2020, 22 patients with pituitary adenomas who underwent endoscopic skull base repair with a Polymax RAPID plate were included. After endonasal transsphenoidal surgery, a trimmed bioresorbable plate was placed in the position between the dura and the bone of the skull base to reconstruct the sellar floor and buttress the pituitary gland and sellar packing. The patient demographics, radiologic imaging, and postoperative outcomes were carefully reviewed. All patients were followed up by a routine nasal endoscopic assessment and radiologic examinations. RESULTS: The present study comprised 10 (45.5%) males and 12 (54.4%) females with an average age of 51.9 years. There were 7 (31.8%) growth hormone (GH) secreting adenomas, 2 (9.1%) thyroid stimulating hormone (TSH) secreting adenomas, and 13 (59.1%) non-functioning adenomas. Enlarged sellar floor and paranasal sinusitis were seen in 13 (59.1%) and 11 (50.0%) cases shown by preoperative computed tomography (CT) or magnetic resonance imaging (MRI), respectively. There were 6 (27.3%) grade-1 and 16 (72.7%) grade-0 cases by intraoperative cerebrospinal fluid (CSF) leak grading. None of these patients received lumbar drains postoperatively and no postoperative CSF rhinorrhea was detected in our series. The PolyMax RAPID plates which could be clearly identified on postoperative CT or sagittal T1-weighted MRI were shown to provide an ideal rigid buttress for sellar repair. CONCLUSIONS: The Polymax RAPID plate can be an optimal implant to achieve rigid repair of sellar floor defects after endonasal transsphenoidal pituitary surgery.

miR-6858 plays a key role in the process of melatonin inhibition of the malignant biological behavior of glioma.

MicroRNAs (miRNAs), small non-coding RNA molecules with a length of 18-25 nucleotides, have been shown to be involved in mediating various malignant properties of GBM, including growth, invasion and angiogenesis. Here, we investigated whether miRNAs might be involved in mediating the suppression of malignant properties of GBM by melatonin (MEL), an amine hormone secreted by the pineal gland. Sequencing was performed to screen specifically for miRNAs induced by MEL in U87 and an orthotopically xenografted primary GBM cell line, GBM#P3. MiR-6858-5p was the most significantly up-regulated miR in GBM cell lines in response to MEL (~5 × ). Transfection of a mimic of miR-6858-5p into both cell lines led to a decrease in viability of ~ 50% at 72 h, confirming a suppressive role for miR-6858-5p in GBM. In contrast, an inhibitor of miR-6858-5p rescued GBM cells from MEL suppression of proliferation, migration and invasion. Analysis using Targetscan yielded candidate mRNAs targeted by miR-6858-5p, some of which are involved in the SIRT/AKT signaling pathway. In cells transfected with a mimic or an inhibitor of miR-6858-5p, levels of SIRT3 and downstream components of the AKT signaling pathway were suppressed or up-regulated, respectively, both in vitro and in an in vivo orthotopic xenograft model. Our results elucidated a novel molecular mechanism underlying MEL suppression of GBM, highlighting a role for miRNAs, and provide a potential therapeutic strategy for GBM.

Glioblastoma Therapy Using Codelivery of Cisplatin and Glutathione Peroxidase Targeting siRNA from Iron Oxide Nanoparticles.

Glioblastoma (GBM) is the most common and lethal type of malignant brain tumor in adults. Currently, interventions are lacking, the median overall survival of patients with GBM is less than 15 months, and the postoperative recurrence rate is greater than 60%. We proposed an innovative local chemotherapy involving the construction of gene therapy-based iron oxide nanoparticles (IONPs) as a treatment for patients with glioblastoma after surgery that targeted ferroptosis and apoptosis to address these problems. The porous structure of IONPs with attached carboxyl groups was modified for the codelivery of small interfering RNA (siRNA) targeting glutathione peroxidase 4 (si-GPX4) and cisplatin (Pt) with high drug loading efficiencies. The synthesized folate (FA)/Pt-si-GPX4@IONPs exerted substantial effects on glioblastoma in U87MG and P3#GBM cells, but limited effects on normal human astrocytes (NHAs). During intracellular degradation, IONPs significantly increased iron (Fe2+ and Fe3+) levels, while Pt destroyed nuclear DNA and mitochondrial DNA, leading to apoptosis. Furthermore, IONPs increased H2O2 levels by activating reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). The Fenton reaction between Fe2+, Fe3+, and intracellular H2O2 generated potent reactive oxygen species (ROS) to initiate ferroptosis, while the co-released si-GPX4 inhibited GPX4 expression and synergistically improved the therapeutic efficacy through a mechanism related to ferroptosis. As a result, superior therapeutic effects with low systemic toxicity were achieved both in vitro and in vivo, indicating that our nanoformulations might represent safe and efficient ferroptosis and apoptosis inducers for use in combinatorial glioblastoma therapy.

Patients with true mixed growth hormone and prolactin-secreting pituitary adenoma: a case series of 12 patients.

Objective: Mixed growth hormone (GH) and prolactin (PRL) secreting adenomas are the most common type of plurihormonal pituitary adenomas. We assessed the clinical presentations and impacts of transsphenoidal surgery (TS) on patients with mixed GH and PRL adenomas including surgical outcomes, complications, and prognosis.Method and patients: Twelve patients (7 males, 5 females) were operated in the neurosurgery department of Qilu hospital affiliated to Shandong University, Shandong, China. We analyzed hormone levels of preoperation, postoperation (within 24 h) and at 12-month follow-up and correlated levels with tumor volumes.Results: The remission rate was 66.7% (8/12), the recurrence rate was 16.7% (2/12), the cause-specific mortality was 0 and the overall mortality rate was 16.7% (2/12) due to stroke and myocardial infarction respectively. A significant drop was seen in GH, PRL, and Insulin-like-growth-factor-1 (IGF-1) levels between preoperation and postoperation with mean values from 52.6 to 9.9 ng/ml (p = 0.0015), from 321.6 to 190.9 ng/ml (p = 0.0026) and from 815.7 to 230.6 ng/ml (p = 0.0004), respectively. This drop was more significant between preoperation and follow-up with mean values from 52.6 to 3.0 ng/ml (p = 0.002), from 321.6 to 61.6 ng/ml (p < 0.0001), and from 815.7 to 195.0 ng/ml (p = 0.0001), respectively. However, there was no significant correlation between tumor volume and all of the hormone levels.Conclusions: Most mixed GH and PRL adenomas are aggressive with a high risk of recurrence and mortality.

Reduced expression of proteolipid protein 2 increases ER stress-induced apoptosis and autophagy in glioblastoma.

Proteolipid protein 2 (PLP2) is an integral ion channel membrane protein of the endoplasmic reticulum. The protein has been shown to be highly expressed in many cancer types, but its importance in glioma progression is poorly understood. Using publicly available datasets (Rembrandt, TCGA and CGGA), we found that the expression of PLP2 was significantly higher in high-grade gliomas than in low-grade gliomas. We confirmed these results at the protein level through IHC staining of high-grade (n = 56) and low-grade glioma biopsies (n = 16). Kaplan-Meier analysis demonstrated that increased PLP2 expression was associated with poorer patient survival. In functional experiments, siRNA and shRNA PLP2 knockdown induced ER stress and increased apoptosis and autophagy in U87 and U251 glioma cell lines. Inhibition of autophagy with chloroquine augmented apoptotic cell death in U87- and U251-siPLP2 cells. Finally, intracranial xenografts derived from U87- and U251-shPLP2 cells revealed that loss of PLP2 reduced glioma growth in vivo. Our results therefore indicate that increased PLP2 expression promotes GBM growth and that PLP2 represents a potential future therapeutic target.

The Natural Flavonoid Galangin Elicits Apoptosis, Pyroptosis, and Autophagy in Glioblastoma.

Galangin (GG), a flavonoid, elicits a potent antitumor activity in diverse cancers. Here, we evaluated the efficacy of GG in the treatment of human glioblastoma multiforme (GBM) and investigated the molecular basis for its inhibitory effects in the disease. GG inhibited viability and proliferation of GBM cells (U251, U87MG, and A172) in a dose-dependent manner (IC50 = 221.8, 262.5, 273.9 µM, respectively; P < 0.001; EdU, ~40% decrease at 150 µM, P < 0.001), and the number of colonies formed was significantly reduced (at 50 µM, P < 0.001). However, normal human astrocytes were more resistant to its cytotoxic effects (IC50 >450 µM). Annexin-V/PI staining was increased indicating that GG induced apoptosis in GBM cells (26.67 and 30.42%, U87MG and U251, respectively) and associated proteins including BAX and cleaved PARP-1 were increased (~3×). Cells also underwent pyroptosis as determined under phase-contrast microscopy. Knockdown of gasdermin E (GSDME), a protein involved in pyroptosis, alleviated pyroptosis induced by GG through aggravating nuclear DNA damage in GBM cells. Meanwhile, fluorescent GFP-RFP-MAP1LC3B puncta associated with autophagy increased under GG treatment, and transmission electron microscopy confirmed the formation of autophagic vesicles. Inhibition of autophagy enhanced GG-induced apoptosis and pyroptosis in GBM cells. Finally, in an orthotopic xenograft model in nude mice derived from U87MG cells, treatment with GG in combination with an inhibitor of autophagy, chloroquine, suppressed tumor growth, and enhanced survival compared to GG monotherapy (P < 0.05). Our results demonstrated that GG simultaneously induces apoptosis, pytoptosis, and protective autophagy in GBM cells, indicating that combination treatment of GG with autophagy inhibitors may be an effective therapeutic strategy for GBM.

Epithelial membrane protein 1 promotes glioblastoma progression through the PI3K/AKT/mTOR signaling pathway.

Glioblastoma multiforme (GBM) is the most malignant intracranial tumor. Although the affected patients are usually treated with surgery combined with radiotherapy and chemotherapy, the median survival time for GBM patients is still approximately 12­14 months. Identifying the key molecular mechanisms and targets of GBM development may therefore lead to the development of improved therapies for GBM patients. In the present study, the clinical significance and potential function of epithelial membrane protein 1 (EMP1) in malignant gliomas were investigated. Increased EMP1 expression was associated with increasing tumor grade (P<0.001) and worse prognosis in patients (P<0.001) based on TCGA, Rembrandt and CGGA databases for human gliomas. In vitro, gene silencing of EMP1 in U87MG and P3 GBM (primary glioma) cells significantly inhibited tumor proliferation and invasion. In addition, it was revealed that activation of the PI3K/AKT/mTOR signaling pathway is the driving force of EMP1­promoted glioma progression. Finally, it was demonstrated, using an intracranial GBM animal model, that EMP1 knockdown significantly inhibits tumor growth in vivo and increases overall survival in tumor­bearing animals. Our research provides new insights into the molecular mechanisms underlying EMP1 knockdown­mediated inhibition of GBM cell invasion and raises the possibility that targeting of EMP1 may represent a promising strategy for the treatment of GBM.

Matrine induces senescence of human glioblastoma cells through suppression of the IGF1/PI3K/AKT/p27 signaling pathway.

BACKGROUND: Matrine, a traditional Chinese medicine, has recently been shown to have antitumor properties in diverse cancer cells. Here, we explored the effect of matrine on human glioblastoma multiforme (GBM) cells. METHODS: Glioblastoma multiforme cell lines were treated with matrine to assess proliferation and viability using EdU and CCK8 assays. SA-ß-gal assays were used to evaluate cellular senescence, and a cytokine array and ELISA assay were used to screen for secreted cytokines altered in GBM cells after matrine treatment. Immunohistochemistry and Western blot analysis were performed to evaluate protein levels in matrine-treated cell lines and in samples obtained from orthotopic xenografts. Specific activators of AKT and IGF1 were used to identify the pathways mediating the effect. RESULTS: Matrine potently inhibited growth of GBM cell lines in vitro. Based on in situ assays, growth arrest induced by matrine was primarily achieved through induction of cellular senescence. Matrine treatment led to decreased expression of proteins involved in promoting cell growth, IGF1, PI3K, and pAKT. Exposure of cells to a small molecule activating AKT (SC79) and recombinant IGF1 led to a reduced number of senescent SA-ß-gal-positive cells in the presence of matrine. Finally, matrine inhibited growth of orthotopic xenografts established from luciferase-stable-U251 or luciferase-stable-P3 cells and prolonged overall survival in mice. CONCLUSIONS: These results indicated that matrine arrested cell growth through inhibition of IGF1/PI3K/AKT signaling. Matrine warrants further investigation as a potential therapy in the treatment of patients with GBM.

Inhibition of glioma growth by flavokawain B is mediated through endoplasmic reticulum stress induced autophagy.

Flavokawain B (FKB), a natural kava chalcone, displays potent antitumor activity in various types of cancer. The mechanism of action, however, remains unclear. Here, we evaluated the efficacy of FKB in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its inhibitory effects in cancer. Approximately 60% of GBM cells became senescent after treatment with FKB as assessed in the senescence-associated (SA)-GLB1/SA-ß-galactosidase assay. The cellular process of autophagy potentially contributed to the establishment of senescence. Transmission electron microscopy revealed the formation of autophagic vesicles under FKB treatment, and MAP1LC3B (microtubule associated protein 1 light chain 3 beta)-II was increased. Transfection of ATG5 or ATG7 small interfering RNAs (siRNAs) inhibited FKB-induced autophagy in U251 cells. Western blot revealed that molecular components of the endoplasmic reticulum stress pathway were activated, including ATF4 (activating transcription factor 4) and DDIT3 (DNA damage inducible transcript 3), while levels of TRIB3 (tribbles pseudokinase 3) increased. In addition, based on the phosphorylation status, the AKT-MTOR-RPS6KB1 pathway was inhibited, which induced autophagy in GBM cells. Inhibition of autophagy by autophagy inhibitors 3-methyladenine and chloroquine or knockdown of ATG5 or ATG7 caused FKB-treated U251 cells to switch from senescence to apoptosis. Finally, knockdown of ATG5 or treatment with chloroquine in combination with FKB, significantly inhibited tumor growth in vivo. Our results demonstrated that FKB induced protective autophagy through the ATF4-DDIT3-TRIB3-AKT-MTOR-RPS6KB1 signaling pathway in GBM cells, indicating that the combination treatment of FKB with autophagy inhibitors may potentially be an effective therapeutic strategy for GBM. ABBREVIATIONS: 3-MA: 3-methyladenine; 4-PBA: 4-phenylbutyrate; AKT: AKT serine/threonine kinase; ATF4: activating transcription factor 4; ATG: autophagy related; CASP3: caspase 3; CCK-8: cell counting kit-8; CDKN1A: cyclin-dependent kinase inhibitor 1A; CQ: chloroquine; DDIT3: DNA damage inducible transcript 3; DMEM: Dulbecco's modified Eagle's medium; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; FKB: flavokawain B; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBM: glioblastoma multiforme; GFP: green fluorescent protein; HSPA5: heat shock protein family A (Hsp70) member 5; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PARP1: poly(ADP-ribose) polymerase; 1RPS6KB1: ribosomal protein S6 kinase B1; SA-GLB1: senescence-associated galactosidase beta 1; siRNA: short interfering RNA; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TRIB3: tribbles pseudokinase 3; TUNEL: deoxynucleotidyl transferase-mediated dUTP nick-end labeling.

Impact of VEGFA polymorphisms on glioma risk in Chinese.

Several single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor A (VEGFA) gene have been previously reported to be associated with glioma susceptibility, but individual studies have demonstrated inconclusive results. In the current study, a meta-analysis was performed to derive a more precise estimation of the involvement of VEGFA polymorphisms in glioma development. A comprehensive literature search conducted in PubMed, Embase, the Cochrane Library, and OVID databases through February 25, 2017 yielded 4 eligible studies consisting of 2,275 cases and 2,475 controls. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated under allele contrast, dominant, recessive, homozygous, and heterozygous models. In general, minor alleles of polymorphisms rs3025039, rs2010963, and rs3025030 were associated with increased glioma risk. In contrast, a significant correlation was found between the minor allele of polymorphism rs3024994 and decreased susceptibility to glioma. Moreover, statistically significant associations with glioma risk were observed for polymorphisms rs1413711 and rs3025035 in the meta-analysis although positive associations were not observed in any of the included studies individually. No significant correlations with glioma susceptibility were identified for polymorphisms rs3025010 or rs833069 except in the recessive model. Finally, stratified analysis on the basis of genotyping method and Hardy-Weinberg equilibrium (HWE) in controls revealed no significant difference between subgroups. Our results indicated that several VEGFA polymorphisms might be risk factors for glioma in Chinese. More studies with larger sample sizes using different ethnicities are needed to provide additional evidence.

Increased NG2 and SOX2 expression is associated with high-grade choroid plexus tumors.

The World Health Organization classification of choroid plexus tumors (CPT) includes three distinct grades: Choroid plexus papilloma (CPP), atypical choroid plexus papilloma (ACPP) and choroid plexus carcinoma (CPC). The molecular basis for these pathological distinctions may help to stratify tumors and provide an insight into the clinical behavior of CPTs. In the present study, the progenitor and stem cell markers neuron glia antigen-2 (NG2) and sex-determining region Y-box 2 (SOX2) were investigated as potential biomarkers that may distinguish between distinct CPT grades. Immunohistochemistry was used to determine the expression of NG2 and SOX2 in CPTs (n=34) from Chinese patients (21 males and 13 females) with a mean age of 31.1 years (range, 1-63 years). The proportion of cells stained were scored using a scale between 0 and 3+, where 0 represents no staining and 3+ represents strong staining, and mean scores for each marker were determined on the basis of tumor grade. Pathological diagnosis revealed a distribution of cases as follows: CPP, 25; ACPP, 5; and CPC, 4. NG2 and SOX2 were expressed in CPTs of all grades. The mean labeling indices for CPP, ACPP and CPC were 1.12, 1.80 and 2.75 for NG2, respectively, and 1.20, 2.00 and 3.00 for SOX2, respectively. Statistical analysis of the mean labeling indices revealed a significant association between the expression of NG2 and SOX2 and CPT grade (P=0.001 and <0.001 for CPP/ACPP and CPP/CPC, respectively). The results of the present study indicated that increased expression of NG2 and SOX2 was associated with higher-grade tumors and that these markers may be useful in determining CPT grade.

Associations of five polymorphisms in the CD44 gene with cancer susceptibility in Asians.

CD44 polymorphisms have been previously associated with cancer risk. However, the results between independent studies were inconsistent. Here, a meta-analysis was performed to systematically evaluate associations between CD44 polymorphisms and cancer susceptibility. A comprehensive literature search conducted in PubMed, Embase, and Web of Science databases through August 10, 2016 yielded 11 eligible publications consisting of 5,788 cancer patients and 5,852 controls. Overall, odds ratios (OR) calculated with 95% confidence intervals (CI) identified a significant association between CD44 polymorphism rs13347 and cancer susceptibility under all genetic models. Additionally, the minor allele of polymorphism rs11821102 was associated with a decreased susceptibility to cancer in allele contrast, dominant, and heterozygous models, while no significant association was identified for polymorphisms rs10836347, rs713330, or rs1425802. Subgroup analysis by ethnicity revealed rs13347 was significantly associated with cancer susceptibility for Chinese but not for Indians. Linkage disequilibrium (LD) between different polymorphisms varied across diverse ethnic populations. In conclusion, the results indicate that CD44 polymorphism rs13347 acts as a risk factor for cancer, especially in Chinese, while the minor allele of polymorphism rs11821102 may be associated with a decreased susceptibility to cancer. Nevertheless, further studies on a larger population covering different ethnicities are warranted.

APOBEC3 deletion increases the risk of breast cancer: a meta-analysis.

Recently, a deletion in the human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) gene cluster has been associated with a modest increased risk of breast cancer, but studies yielded inconsistent results. Therefore we performed a meta-analysis to derive a more precise conclusion. Six studies including 18241 subjects were identified by searching PubMed and Embase databases from inception to April 2016. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were evaluated under allele contrast, dominant, recessive, homozygous, and heterozygous models. All the analyses suggested a correlation of APOBEC3 deletion with increased breast cancer risk (D vs I: OR = 1.29, 95% CI = 1.23-1.36; D/D+I/D vs I/I: OR = 1.34, 95% CI = 1.26-1.43; D/D vs I/D+ I/I: OR = 1.51, 95% CI = 1.36-1.68; D/D vs I/I: OR = 1.75, 95% CI= 1.56-1.95; I/D vs I/I: OR = 1.28, 95% CI = 1.19-1.36). Stratified analysis by ethnicity showed that the relationship is stronger and more stable in Asians. In summary, our current work indicated that APOBEC3 copy number variations might have a good screening accuracy for breast cancer.

Berberine induces autophagy in glioblastoma by targeting the AMPK/mTOR/ULK1-pathway.

There is an urgent need for new therapeutic strategies for patients with glioblastoma multiforme (GBM). Previous studies have shown that berberine (BBR), a natural plant alkaloid, has potent anti-tumor activity. However, the mechanisms leading to cancer cell death have not been clearly elucidated. In this study, we show that BBR has profound effects on the metabolic state of GBM cells, leading to high autophagy flux and impaired glycolytic capacity. Functionally, these alterations reduce the invasive properties, proliferative potential and induce apoptotic cell death. The molecular alterations preceding these changes are characterized by inhibition of the AMPK/mTOR/ULK1 pathway. Finally, we demonstrate that BBR significantly reduces tumor growth in vivo, demonstrating the potential clinical benefits for autophagy modulating plant alkaloids in cancer therapy.

Nitidine chloride inhibits the malignant behavior of human glioblastoma cells by targeting the PI3K/AKT/mTOR signaling pathway.

Recent studies have demonstrated that nitidine chloride (NC), a natural bioactive alkaloid, displays potent antitumor activity in various types of cancer. In the present study, NC was examined for efficacy in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its more general inhibitory effects in cancer. U251 and U87 GBM cell lines were exposed to three concentrations of NC (5, 25 and 50 µM) in vitro, and tumor cell growth was assessed on the basis of proliferation, migration and energy metabolism. Decreases in viability and proliferation reached ~50% for both cell lines with 50 µM NC at 24 h as assessed by cell viability Cell Counting Kit-8 (CCK-8) and EdU assays. In wound closure and Transwell assays, migration and invasion were inhibited at 50 µM after 24 h (~20 and 80%, respectively; P<0.05). ATP and L-lactate levels were also decreased after treatment with NC (50 µM, 24 h; P<0.05 and P<0.01, respectively). Finally, in western blot analysis, phosphorylation of Akt and mTOR was suppressed by NC, but partially restored when cells were treated simultaneously with a novel Akt activator, SC79. Partial restoration was also observed in viability/proliferation (U251 and U87, ~15 vs. 40%; NC vs. NC + SC79; P<0.05) and invasion (U251 and U87, ~30 vs. 60%; NC vs. NC + SC79; P<0.05). Our results demonstrated that NC inhibits development of GBM by targeting the PI3K/Akt/mTOR signaling pathway and provides a potential therapeutic agent for the treatment of GBM.