Ribavirin, a nucleic acid analog, has been employed as an antiviral agent against RNA and DNA viruses and has become the standard agent used for chronic hepatitis C in combination with ...interferon-α2a. Furthermore, the potential antitumor efficacy of ribavirin has attracted increasing interest. Recently, we demonstrated a dose-dependent antitumor effect of ribavirin for seven types of malignant glioma cell lines. However, the mechanism underlying the antitumor effect of ribavirin has not yet been fully elucidated. Therefore, the main aim of the present study was to provide further relevant data using two types of malignant glioma cell lines (U-87MG and U-138MG) with different expression of MGMT. Dotted accumulations of γH2AX were found in the nuclei and increased levels of ATM and phosphorylated ATM protein expression were also observed following ribavirin treatment (10 µM of ribavirin, clinical relevant concentration) in both the malignant glioma cells, indicating double-strand breaks as one possible mechanism underlying the antitumor effect of ribavirin. In addition, based on assessements using FACS, ribavirin treatment tended to increase the G0/G1 phase, with a time‑lapse, indicating the induction of G0/G1-phase arrest. Furthermore, an increased phosphorylated p53 and p21 protein expression was confirmed in both glioma cells. Additionally, analysis by FACS indicated that apoptosis was induced following ribavirin treatment and caspase cascade, downstream of the p53 pathway, which indicated the activation of both exogenous and endogenous apoptosis in both malignant glioma cell lines. These findings may provide an experimental basis for the clinical treatment of glioblastomas with ribavirin.
We report here a rare case of symptomatic granular cell tumor (GCT) of the sellar region with a large calcification. A 70‐year‐old woman presented with a sellar mass, accompanied by bitemporal ...hemianopia. The patient was diagnosed preoperatively as having a craniopharyngioma or a pituitary adenoma, because of the large calcification. The patient underwent surgical tumor resection via endoscopic trans‐sphenoidal surgery and was diagnosed pathologically as having GCT. The patient's postoperative course was uneventful and her visual field disturbance improved soon after the operation. We briefly discuss the pathological discrimination of GCT and other sellar tumors, since there are many unclear points concerning this rare tumor.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Interferon β (IFN‐β) is considered a signaling molecule with important therapeutic potential in cancer since IFN‐β‐induced gene transcription mediates antiproliferation and cell death induction. ...Whereas, TNF‐related apoptosis inducing ligand/Apo2 ligand (TRAIL/Apo2L) has emerged as a promising anticancer agent because it induces apoptosis specifically in cancer cells. In this study, we elucidated that IFN‐β augments TRAIL‐induced apoptosis synergistically using five human malignant melanoma cells. All of these cells were induced apoptosis by TRAIL. Whereas, the response against IFN‐β was different in amelanotic cells (A375 and CRL1579) and melanotic cells (G361, SK‐MEL‐28, and MeWo). The responsibility of amelanotic cells against IFN‐β was higher than those of melanotic cells. The synergism of IFN‐β and TRAIL were correlated with the responsibilities of the cells against IFN‐β. The synergistic interaction was confirmed by a combination index based on the Chou‐Talalay method. The upregulation of apoptosis in amelanotic cells was caused by very low doses of IFN‐β (over 0.1 IU/ml). Both of p53‐mediated intrinsic pathway and Fas‐related extrinsic pathway were activated by IFN‐β alone and combination with TRAIL. Further, TRAIL death receptors (DR4 and DR5) were upregulated by a low‐dose IFN‐β (over 0.1 IU/ml) and the expression was more promoted by the combination with TRAIL. It was clarified that the upregulation of DR5 is associated with the declination of viability.
Interferon β (IFN‐β) promotes TNF‐related apoptosis inducing ligand/Apo2 ligand (TRAIL/Apo2L)‐induced apoptosis synergically. The augmentation by IFN‐β was associated with the activation of Fas, p53, and TRAIL apoptotic signaling pathways.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Interleukin-6 (IL-6) enhanced TNF-α and TRAIL/Apo2L induced cell death in various human cancer cells derived from malignant glioma, melanoma, breast cancer and leukemia, although the effect was not ...detected with IL-6 alone. The effects of IL-6 using SKBR3 cells were associated with the generation of apoptotic cells as analyzed by fluorescence microscopy and flow cytometry. IL-6 activated p53 and upregulated TRAIL death receptors (DR-4 and DR-5) and stimulated the TNF-α and TRAIL dependent extrinsic apoptotic pathway without activation of the p53 mediated intrinsic apoptotic pathway. TNF-α and TRAIL induced cleavage of caspase-8 and caspase-3 was more enhanced by IL-6, although these caspases were not cleaved by IL-6 alone. The dead cell generation elicited by the combination with IL-6 was blocked by anti-human TRAIL R2/TNFRSF10B Fc chimera antibody which can neutralize the DR-5 mediated death signal. These findings indicate that IL-6 could contribute to the enhancement of TNF-α or TRAIL induced apoptosis through p53 dependent upregulation of DR-4 and DR-5. The data suggest that a favorable therapeutic interaction could occur between TNF-α or TRAIL and IL-6, and provide an experimental basis for rational clinical treatments in various cancers.
•IL-6 enhanced TNF-α and TRAIL/Apo2L induced cell death in human cancer cells.•IL-6 promotes cell death through p53 dependent upregulation of death receptors.•IL-6 sensitizes fas and TRAIL mediated extrinsic apoptotic pathway.•IL-6 enhanced the cleavage of caspase-8 and caspase-9 promoted by TNF-α and TRAIL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent research has revealed that glioblastoma (GBM) avoids the immune system via strong expression of indoleamine 2,3-dioxygenase 1 (IDO1). IDO1, an enzyme involved in tryptophan metabolism, is now ...proposed as a new target in GBM treatment, since several reports have demonstrated that IDO1 expression is related to GBM malignancy. On the other hand, it is well known that glioma stem cells (GSCs) are strongly related to the malignancy of GBM. However, there is as yet no report evaluating the relationship between GSCs and IDO1. We therefore examined the expression levels of IDO1 in GSCs in order to identify a new therapeutic target for GBM based on the immune systems of GSCs. In the present study, we employed human GBM cell lines (U-138MG, U-251MG) and patient-derived GSC model cell lines (0125-GSC, 0222-GSC). GSC model cell lines Rev-U-138MG and Rev-U-251MG were established by culturing U-138MG and U-251MG in serum-free media, while differentiated GBM model cell lines 0125-DGC and 0222-DGC were established by culturing 0125-GSC and 0222-GSC in serum-containing media. The expression levels of stem cell markers (Nanog, Nestin, Oct4 and Sox2) and IDO1 protein and mRNA were determined. Rev-U-138MG and Rev-U-251MG formed spheres and their expression levels of stem cell markers were increased as compared to U-138MG and U-251MG. On the other hand, 0125-DGC and 0222-DGC suffered breakdown of sphere formation, despite the original 0125-GSC and 0222-GSC forming spheres, and their expression levels of the markers were decreased. IDO1 expressions were strongly recognized in Rev-U-138MG, Rev-U-251MG, 0125-GSC and 0222-GSC as compared to U-138MG, U-251MG, 0125-DGC and 0222-DGC. These findings demonstrate that GSCs exhibit treatment resistance with immunosuppression via high expression levels of IDO1, and could represent a novel target for GBM treatment.
•IDO1 is highly expressed in glioma stem cells.•Glioma stem cells suppress the immune system via IDO1 expression.•IDO1 expression is related to GBM differentiation state.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients with glioblastoma frequently suffer epileptic seizures and often require anticonvulsant therapy during the treatment course. The present study investigated four common antiepileptic drugs, ...perampanel, carbamazepine (CBZ), sodium valproate (VPA) and levetiracetam (LEV), which are expected to have antitumor effects, and determined the most beneficial drug for the treatment of malignant glioma by comparing antitumor effects such as inhibition of cell proliferation and suppression of migration and invasion (using Transwell assays). The inhibition of cell growth was investigated using six malignant glioma cell lines (A-172, AM-38, T98G, U-138MG, U-251MG and YH-13). Significant inhibition of cell proliferation was observed in all six cell lines treated with perampanel, three cell lines treated with CBZ, four cell lines treated with VPA and two cell lines treated with LEV at the therapeutic blood concentration levels for the drugs to be used as antiepileptics. Further antitumor effects in combination with temozolomide were investigated using T98G and U-251MG cell lines, and were confirmed in both cell lines with perampanel and in T98G cells with LEV, but not observed with CBZ and VPA. Cell migration was significantly suppressed in both T98G and U-251MG cell lines with perampanel, but not with CBZ, VPA or LEV. To investigate the mechanisms by which perampanel suppresses the migration of malignant glioma cells, the expression of mRNA related to epithelial-mesenchymal transition following perampanel treatment was analyzed using reverse transcription-quantitative PCR in the T98G and U-251MG cell lines. The expression of Rac1 and RhoA, which constitute the cytoskeleton that enhances cell motility, were reduced in both cell lines. Furthermore, the expression of the mesenchymal marker N-cadherin, which promotes cell migration and infiltration, was decreased, but the expression of the epithelial marker E-cadherin, which strengthens cell-cell adhesion and reduces cell motility, was increased. Furthermore, the expression of matrix metalloproteinase-2, a proteolytic enzyme, was reduced. These effects may reduce cell motility and increase adhesion between cells, suggesting that perampanel treatment suppressed cell migration. In conclusion, the present study suggests that perampanel may be more beneficial in terms of antitumor efficacy than other antiepileptic drugs for the treatment of malignant glioma.
Pituitary apoplexy is an acute clinical syndrome caused by infarction and/or hemorrhage of pituitary adenoma, which typically presents with severe headache, visual deterioration, and endocrine ...abnormalities. However, temporal lobe seizure (and temporal lobe epilepsy) has not been viewed as a symptom of pituitary apoplexy in the literature.
To elucidate further such a rare complication of temporal lobe seizure, we describe here the rare clinical manifestations of a 55-year-old previously healthy man with pituitary apoplexy harboring headache, combined palsies involving cranial nerves III to VI, endocrinologic disturbances, and temporal lobe seizure. In addition, we discuss the temporal lobe seizure (and temporal lobe epilepsy) associated with pituitary adenoma based on the literature.
Although further accumulation of clinical data is needed, we would like to emphasize the importance of recognition of temporal lobe seizure caused by pituitary apoplexy, and to suggest that early surgery could be considered as an option in patients displaying such a rare complication.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in cancer cells by binding to its receptors, death receptor 4 ...(DR4) and DR5, without affecting normal cells, and is therefore considered to be a promising antitumor agent for use in cancer treatment. However, several studies have indicated that most glioma cell lines display resistance to TRAIL‑induced apoptosis. To overcome such resistance and to improve the efficacy of TRAIL‑based therapies, identification of ideal agents for combinational treatment is important for achieving rational clinical treatment in glioblastoma patients. The main aim of this study was to investigate whether interferon‑β (IFN‑β) (with its pleiotropic antitumor activities) could sensitize malignant glioma cells to TRAIL‑induced apoptosis using glioma cell lines. TRAIL exhibited a dose‑dependent antitumor effect in all of the 7 types of malignant glioma cell lines, although the intensity of the effect varied among the cell lines. In addition, combined treatment with TRAIL (low clinical dose: 1 ng/ml) and IFN‑β (clinically relevant concentration: 10 IU/ml) in A‑172, AM‑38, T98G, U‑138MG and U‑251MG demonstrated a more marked antitumor effect than TRAIL alone. Furthermore, the antitumor effect of the combined treatment with TRAIL and IFN‑β may be enhanced via an extrinsic apoptotic system, and upregulation of DR5 was revealed to play an important role in this process in U‑138MG cells. These findings provide an experimental basis to suggest that combined treatment with TRAIL and IFN‑β may offer a new therapeutic strategy for malignant gliomas.
Abstract
BACKGROUND
Embryonal tumor with multilayered rosettes (ETMR) is a rare, highly malignant tumor of the central nervous system and is usually diagnosed in children aged <2 years. Currently, ...because no defined treatment strategy has been reported, treatment regimens are often extrapolated from other embryonal tumors. Therefore, data collection of ETMR cases is important for further understanding EMTR. Here, we present our experience with four patients with ETMR.
MATERIAL AND METHODS
Patients with a pathological diagnosis of ETMR from 1999 to 2016 at Saitama Children’s Medical Center were included. Their clinical data were retrospectively analyzed.
RESULTS
This study included four cases of ETMR (one male and three females). The mean age at diagnosis was 29.5 (range, 15–37) months. Presenting symptoms included seizure, hemiparesis, vomiting, and headache. The mean maximal tumor diameter was 42.5 mm. The tumor locations included frontal lobe, temporal lobe, occipital lobe, cerebellum, and brainstem. Gross total resection was achieved in two cases. Fluorescence in situ hybridization analysis demonstrated amplification of 19q13.42 chromosome region in all cases, and diffuse positive expression was observed in the immunohistochemical staining for LIN28A. Systemic postoperative chemotherapy was administered to all patients. Three patients received intrathecal therapy and three were irradiated. The mean overall survival and progression-free survival were 45.3 and 42 months, respectively. Two patients who underwent gross total resection are alive without recurrence.
CONCLUSION
Complete surgical resection may be an important prognostic factor in patients with ETMR. Further prospective studies are needed to confirm these results.
Glioblastoma is a malignant brain tumor exhibiting highly aggressive proliferation and invasion capacities. Despite treatment by aggressive surgical resection and adjuvant therapy including ...temozolomide and radiation therapy, patient prognosis remains poor. Lenalidomide, a derivative of thalidomide, is known to be an immunomodulatory agent that has been used to treat hematopoietic malignancies. There are numerous studies revealing an antitumor effect of lenalidomide in hematopoietic cells, but not in glioma cells. The present study aimed to demonstrate the antitumor effect of lenalidomide on malignant glioma cell lines. The growth inhibition of malignant glioma cells (A‑172, AM‑38, T98G, U‑138MG, U‑251MG, and YH‑13) by lenalidomide was assessed using a Coulter counter. The mechanism of the antitumor effect of lenalidomide was examined employing a fluorescence‑activated cell sorter, western blot analysis, and quantitative real‑time reverse transcriptional polymerase chain reaction (RT‑qPCR) in malignant glioma cell lines (A‑172, AM‑38). The results revealed that the number of malignant glioma cells was decreased in a concentration‑dependent manner by lenalidomide. DNA flow cytometric analysis demonstrated an increase in the ratio of cells at the G0/G1 phase following lenalidomide treatment. Western blot analysis and RT‑qPCR revealed that p53 activation and the expression of p21 were increased in glioma cells treated with lenalidomide. Western blot analysis revealed that cleavage of PARP did not occur; however, increased expression of Bax protein, cleavage of caspase‑9 and cleavage of caspase‑3 were confirmed. Analysis by FACS also supported the conclusion that little apoptosis induction occurred following lenalidomide treatment of malignant glioma cell lines. In conclusion, lenalidomide exerts an antitumor effect on glioma cells due to alterations in cell cycle distribution.
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