Lestaurtinib potentiates TRAIL-induced apoptosis in glioma via CHOP-dependent DR5 induction.

Lestaurtinib, also called CEP-701, is an inhibitor of tyrosine kinase, causes haematological remission in patients with AML possessing FLT3-ITD (FLT3 gene) internal tandem duplication and strongly inhibits tyrosine kinase FLT3. Treatment with lestaurtinib modulates various signalling pathways and leads to cell growth arrest and programmed cell death in several tumour types. However, the effect of lestaurtinib on glioma remains unclear. In this study, we examined lestaurtinib and TRAIL interactions in glioma cells and observed their synergistic activity on glioma cell apoptosis. While U87 and U251 cells showed resistance to TRAIL single treatment, they were sensitized to apoptosis induced by TRAIL in the presence of lestaurtinib because of increased death receptor 5 (DR5) levels through CHOP-dependent manner. We also demonstrated using a xenograft model of mouse that the tumour growth was absolutely suppressed because of the combined treatment compared to TRAIL or lestaurtinib treatment carried out singly. Our findings reveal a potential new strategy to improve antitumour activity induced by TRAIL in glioma cells using lestaurtinib through a mechanism dependent on CHOP.

CDK4/6 inhibition suppresses tumour growth and enhances the effect of temozolomide in glioma cells.

In adults, glioma is the most commonly occurring and invasive brain tumour. For malignant gliomas, the current advanced chemotherapy includes TMZ (temozolomide). However, a sizeable number of gliomas are unyielding to TMZ, hence, giving rise to an urgent need for more efficient treatment choices. Here, we report that cyclin-dependent kinases 4 (CDK4) is expressed at significantly high levels in glioma cell lines and tissues. CDK4 overexpression enhances colony formation and proliferation of glioma cells and extends resistance to inhibition of TMZ-mediated cell proliferation and induction of apoptosis. However, CDK4 knockdown impedes colony formation and cell proliferation, and enhances sensitivity of glioma cells to TMZ. The selective inhibition of CDK4/6 impedes glioma cell proliferation and induces apoptotic induction. The selective inhibitors of CDK4/6 may enhance glioma cell sensitivity to TMZ. We further showed the possible role of RB phosphorylation mediated by CDK4 for its oncogenic function in glioma. The growth of glioma xenografts was inhibited in vivo, through combination treatment, and corresponded to enhanced p-RB levels, reduced staining of Ki-67 and enhanced activation of caspase 3. Therefore, CDK4 inhibition may be a favourable strategy for glioma treatment and overcomes TMZ resistance.

miR-152-5p suppresses glioma progression and tumorigenesis and potentiates temozolomide sensitivity by targeting FBXL7.

A generally used chemotherapeutic drug for glioma, a frequently diagnosed brain tumour, is temozolomide (TMZ). Our study investigated the activity of FBXL7 and miR-152-5p in glioma. Levels of microRNA-152-5p (miR-152-5p) and the transcript and protein of FBXL7 were assessed by real-time PCR and Western blotting, respectively. The migratory and invasive properties of cells were measured by Transwell migration and invasion assay and their viability were examined using CCK-8 assay. Further, the putative interaction between FBXL7 and miR-152-5p were analysed bioinformatically and by luciferase assay. The activities of FBXL7, TMZ and miR-152-5p were analysed in vivo singly or in combination, on mouse xenografts, in glioma tumorigenesis. The expression of FBXL7 in glioma tissue is significantly up-regulated, which is related to the poor prognosis and the grade of glioma. TMZ-induced cytotoxicity, proliferation, migration and invasion in glioma cells were impeded by the knock-down of FBXL7 or overexpressed miR-152-5p. Furthermore, the expression of miR-152-5p reduced remarkably in glioma cells and it exerted its activity through targeted FBXL7. Overexpression of miR-152-5p and knock-down of FBXL7 in glioma xenograft models enhanced TMZ-mediated anti-tumour effect and impeded tumour growth. Thus, the miR-152-5p suppressed the progression of glioma and associated tumorigenesis, targeted FBXL7 and increased the effect of TMZ-induced cytotoxicity in glioma cells, further enhancing our knowledge of FBXL7 activity in glioma.

MiR-3116 sensitizes glioma cells to temozolomide by targeting FGFR1 and regulating the FGFR1/PI3K/AKT pathway.

Glioma is a brain tumour that is often diagnosed, and temozolomide (TMZ) is a common chemotherapeutic drug used in glioma. Yet, resistance to TMZ is a chief hurdle towards curing the malignancy. The current work explores the pathways and involvement of miR-3116 in the TMZ resistance. miR-3116 and FGFR1 mRNA were quantified by real-time PCR in malignant samples and cell lines. Appropriate assays were designed for apoptosis, viability, the ability to form colonies and reporter assays to study the effects of the miR-3116 or FGFR1. The involvement of PI3K/AKT signalling was assessed using Western blotting. Tumorigenesis was evaluated in an appropriate xenograft mouse model in vivo. This work revealed that the levels of miR-3116 dipped in samples resistant to TMZ, while increased miR-3116 caused an inhibition of the tumour features mentioned above to hence augment TMZ sensitivity. miR-3116 was found to target FGFR1. When FGFR1 was overexpressed, resistance to TMZ was augmented and reversed the sensitivity caused by miR-3116. Our findings further confirmed PI3K/AKT signalling pathway is involved in this action. In conclusion, miR-3116 sensitizes glioma cells to TMZ through FGFR1 downregulation and the PI3K/AKT pathway inactivation. Our results provide a strategy to overcome TMZ resistance in glioma treatment.

miR-1254 inhibits progression of glioma in vivo and in vitro by targeting CSF-1.

The role of miRNAs (microRNAs) has been implicated in glioma initiation and progression, although the inherent biochemical mechanisms still remain to be unravelled. This study strived to evaluate the association between CSF-1 and miR-1254 and their effect on advancement of glioma cells. The levels of miR-1254 in glioma cells and tissues were determined by real-time RT-PCR. Proliferation, apoptosis and cell cycle arrest, invasion and migration, were assessed by CCK-8 assay, colony formation assay, flow cytometry, transwell assay and wound-healing assay, respectively. The targeted relationship between miR-1254 and CSF-1 was confirmed by dual-luciferase reporter assay. The effects of CSF-1 on cellular functions were also assessed. The in vivo effect of miR-1254 on the formation of a tumour was explored by using the mouse xenograft model. We found in both glioma tissues and glioma cells, the down-regulated expressions of miR-1254 while that of CSF-1 was abnormally higher than normal level. The target relationship between CSF-1 and miR-1254 was validated by dual-luciferase reporter assay. The CSF-1 down-regulation or miR-1254 overexpression impeded the invasion, proliferation and migratory ability of U251 and U87 glioma cells, concurrently occluded the cell cycle and induced cell apoptosis. Moreover, in vivo tumour development was repressed due to miR-1254 overexpression. Thus, CSF-1 is targeted directly by miR-1254, and the miR-1254/CSF-1 axis may be a potential diagnostic target for malignant glioma.

Effects of preoperative bromocriptine treatment on prolactin-secreting pituitary adenoma surgery.

Pituitary adenomas are benign intracranial endocrine tumors, accounting for ~10% of intracranial tumors. The aim of the present study was to analyze the effects of preoperative treatment with bromocriptine on the surgical treatment and postoperative complications of prolactin-secreting pituitary adenomas (prolactinomas). Data from 102 patients whose prolactinomas were surgically treated between March 2006 and March 2010 were retrospectively reviewed in the present study. The study group included 54 patients who had been treated preoperatively with bromocriptine. The patients were examined by magnetic resonance imaging (MRI) of the head and coronal computed tomography (CT) scanning, after which the pathological diagnosis of prolactinoma was confirmed. A total of 64 patients underwent total resection surgery through the nose and sphenoid sinus, and 25 patients underwent subtotal resection surgery or excision of a large portion of the tumor, leaving only a small quantity of residual tumor or tumor capsule. Patients were followed up for 1-9 months using MRI and measurements of serum prolactin levels. Seven patients were lost to follow-up. The results of the present study demonstrated that patients who were treated with large doses of bromocriptine or used bromocriptine chronically suffered from an increased rate of surgical difficulties and postoperative complications, as compared with the patents who had not been pre-treated with bromocriptine. In conclusion, oral administration of bromocriptine is important in the treatment of prolactinoma tumors. However, large doses or long-term use of bromocriptine may increase difficulties in surgery or postoperative complications, and reduce its ability to treat prolactinonas, as it can lead to hardening of the tumor tissue and capsules, and aggravate pituitary stalk adhesions.