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      Antiglioma effects of cytarabine on leptomeningeal metastasis of high-grade glioma by targeting the PI3K/Akt/mTOR pathway

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          Abstract

          Leptomeningeal metastasis (LM) of high-grade glioma is a highly lethal disease requiring new effective therapeutic measures. For both de novo or relapsed glioma with LM, intrathecal cytarabine chemotherapy is not frequently used for first-line and relapse protocols. We encountered a clinical case demonstrating effective application of cytarabine in high-grade glioma with LM, prompting us to explore the effects of cytarabine on malignant glioma and molecular mechanisms of such effects through in vivo and in vitro experiments. The U87 cell line was selected to represent human glioma for studies. Cell viability was measured by MTT assay, plate colony formation assay, and trypan-blue dye exclusion test. Apoptosis was assessed by flow cytometry. Protein expression levels were detected by Western blot assay and immunohistochemistry. mRNA expression was examined by quantitative real-time reverse transcription polymerase chain reaction. Cytarabine inhibited tumor growth during the in vivo experiment. The present study confirmed that cytarabine inhibits proliferation and promotes apoptosis of U87 cells, and molecular analysis of this effect showed that cytarabine significantly reduces expression of phosphatidylinositol 3-kinase/serine/threonine kinase also known as the protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathway, Ki-67, BCL2, and 4-1BB, and upregulates Bax and cleaved caspase-3. Our findings indicated that intrathecal administration of cytarabine manifests potential in prophylaxis and treatment of malignant glioma with LM. Effective medications for high-grade glioma with LM should contain cytarabine.

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          Most cited references 39

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          Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma

          Background Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown. Results In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRP1 and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol) and etoposide (VP16) compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors. Conclusion Our study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in tumors to improve the survival of brain tumor patients.
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            AKT plays a central role in tumorigenesis.

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              Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype.

              Neural stem cells with astrocyte-like characteristics exist in the human brain subventricular zone (SVZ), and these cells may give rise to glioblastoma multiforme (GBM). We therefore analyzed MRI features of GBMs in specific relation to the SVZ. We reviewed the preoperative and serial postoperative MR images of 53 patients with newly diagnosed GBM. The spatial relationship of the contrast-enhancing lesion (CEL) with the SVZ and cortex was determined preoperatively. Classification was as follows: group I, CEL contacting SVZ and infiltrating cortex; group II, CEL contacting SVZ but not involving cortex; group III, CEL not contacting SVZ but involving cortex; and group IV, CEL neither contacting SVZ nor infiltrating cortex. Patients with group I GBMs (n = 16) were most likely to have multifocal disease at diagnosis (9 patients, 56%, p = 0.001). In contrast, group IV GBMs (n = 14) were never multifocal. Group II (n = 14) and group III (n = 9) GBMs were multifocal in 11% and 29% of cases, respectively. Group I GBMs always had tumor recurrences noncontiguous with the initial lesion(s), while group IV GBM recurrences were always bordering the primary lesion. Group I GBMs may be most related to SVZ stem cells; these tumors were in intimate contact with the SVZ, were most likely to be multifocal at diagnosis, and recurred at great distances to the initial lesion(s). In contrast, group IV GBMs were always solitary lesions; these may arise from non-SVZ, white matter glial progenitors. Our MRI-based classification of GBMs may further our understanding of GBM histogenesis and help predict tumor recurrence pattern.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                26 June 2017
                : 11
                : 1905-1915
                Affiliations
                [1 ]Department of Glioma
                [2 ]Clinical Center of Gene And Cell Engineering, Beijing Shijitan Hospital
                [3 ]Department of Neurosurgery, Beijing Tiantan Hospital
                [4 ]Department of Pathology, Sanbo Brain Hospital, Capital Medical University, Beijing, People’s Republic of China
                Author notes
                Correspondence: Wen-Bin Li, Department of Glioma, Beijing Shijitan Hospital, Capital Medical University, Tieyilu 10, Yangfangdian, Haidian District, Beijing 100038, People’s Republic of China, Email neure55@ 123456126.com
                Article
                dddt-11-1905
                10.2147/DDDT.S135711
                5500519
                © 2017 Zhao et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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