Glioblastoma: Therapeutic challenges, what lies ahead

Lima, Flávia Regina Souza; Kahn, Suzana Assad; Soletti, Rossana C.; Biasoli, Deborah; Alves, Tércia; Fonseca, Anna Carolina Carvalho da; García, Celina; Romão, Luciana; Brito, José M.; Holanda-Afonso, Rosenilde C.; Faria, Jane; Borges, Helena L.; Moura‐Neto, Vivaldo

doi:10.1016/j.bbcan.2012.05.004

Cited by 105 publications

(107 citation statements)

References 128 publications

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“…GCSCs have been described as tumor cells that display stem cell properties, including unlimited self-renewal, tumorigenic potential, asymmetric cell division, and multipotency -the ability to differentiate into both rapidly proliferating progenitor-like cells and more differentiated GBM cells. 2 As these cells are resistant to standard therapy, they are considered a major source of GBM recurrence, which makes them a promising target for novel, more effective therapies.…”

Section: Discussionmentioning

confidence: 99%

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Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

et al. 2015

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Glioblastoma (GBM) is associated with poor prognosis despite aggressive surgical resection, chemotherapy, and radiation therapy. Unfortunately, this standard therapy does not target glioma cancer stem cells (GCSCs), a subpopulation of GBM cells that can give rise to recurrent tumors. GBMs express human cytomegalovirus (HCMV) proteins, and previously we found that the level of expression of HCMV immediate-early (IE) protein in GBMs is a prognostic factor for poor patient survival. In this study, we investigated the relation between HCMV infection of GBM cells and the presence of GCSCs. Primary GBMs were characterized by their expression of HCMV-IE and GCSCs marker CD133 and by patient survival. The extent to which HCMV infection of primary GBM cells induced a GCSC phenotype was evaluated in vitro. In primary GBMs, a large fraction of CD133-positive cells expressed HCMV-IE, and higher co-expression of these two proteins predicted poor patient survival. Infection of GBM cells with HCMV led to upregulation of CD133 and other GSCS markers (Notch1, Sox2, Oct4, Nestin). HCMV infection also promoted the growth of GBM cells as neurospheres, a behavior typically displayed by GCSCs, and this phenotype was prevented by either chemical inhibition of the Notch1 pathway or by treatment with the anti-viral drug ganciclovir. GBM cells that maintained expression of HCMV-IE failed to differentiate into neuronal or astrocytic phenotypes. Our findings imply that HCMV infection induces phenotypic plasticity of GBM cells to promote GCSC features and may thereby increase the aggressiveness of this tumor. GBM is the most prevalent and the most aggressive primary malignancy of the central nervous system in adults. It is a highly vascularized and infiltrating tumor, rarely cured and prone to recurrence. The median duration of survival after diagnosis is less than 15 months, despite aggressive therapy consisting of surgical resection and concomitant radiotherapy and chemotherapy. 1 Surgical resection of GBMs is typically incomplete, as they are located in the brain and are highly infiltrative. Postoperative radiotherapy and chemotherapy fail to eradicate all remaining GBM cells. Thus, a breakthrough in identifying a new treatment option leading to a cure of this disease is still lacking.GBMs contain a subpopulation of highly tumorigenic cells with unlimited capacity for self-renewal that are commonly resistant to standard therapy. Phenotypically and functionally, these cells resemble neural stem cells and, when implanted in immunodeficient mice, can generate new tumors. As a result, they are referred to as glioma cancer initiating cells or glioma cancer stem cells (GCSCs) (reviewed in Lima et al. 2 ).Because of their apparent pivotal role in gliomagenesis and tumor recurrence after therapy, GCSCs are a major focus of research whose ultimate goal is to identify more effective therapies for GBM patients.GCSCs were first identified by their surface expression of CD133, based on the findings that these cells grow as neurospheres under nonadher...

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Section: Discussionmentioning

confidence: 99%

“…Phenotypically and functionally, these cells resemble neural stem cells and, when implanted in immunodeficient mice, can generate new tumors. As a result, they are referred to as glioma cancer initiating cells or glioma cancer stem cells (GCSCs) (reviewed in Lima et al 2 ).…”

mentioning

confidence: 99%

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

et al. 2015

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“…The injection of therapeutic agents into a surgically resected tumor or transient disruption of the blood-brain barrier is a technique suggested to bypass such shortcomings. 28,29 In spite of the clinical and technical progress in glioblastoma therapy, the mortality rate of this tumor remains high. 30 At present, the increasing knowledge of nanotechnology promises to be helpful in the development of localized delivery of therapeutic agents by means of nanocarriers with small particle size.…”

Section: Discussionmentioning

confidence: 99%

Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells

Mirgani¹,

Isacchi²,

Sadeghizadeh³

et al. 2014

IJN

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Glioblastoma is an invasive tumor of the central nervous system. Tumor recurrence resulting from ineffective current treatments, mainly due to the blood–brain barrier, highlights the need for innovative therapeutic alternatives. The recent availability of nanotechnology represents a novel targeted strategy in cancer therapy. Natural products have received considerable attention for cancer therapy because of general lower side effects. Curcumin is a new candidate for anticancer treatment, but its low bioavailability and water solubility represent the main disadvantages of its use. Here, curcumin was efficiently encapsulated in a nontoxic nanocarrier, termed dendrosome, to overcome these problems. Dendrosomal curcumin was prepared as 142 nm spherical structures with constant physical and chemical stability. The inhibitory role of dendrosomal curcumin on the proliferation of U87MG cells, a cellular model of glioblastoma, was evaluated by considering master genes of pluripotency and regulatory miRNA (microribonucleic acid). Methylthiazol tetrazolium assay and flow cytometry were used to detect the antiproliferative effects of dendrosomal curcumin. Annexin-V-FLUOS and caspase assay were used to quantify apoptosis. Real-time polymerase chain reaction was used to analyze the expression of OCT4 (octamer binding protein 4) gene variants ( OCT4A , OCT4B , and OCT4B1 ), SOX-2 (SRY [sex determining region Y]-box 2) , Nanog , and miR-145 . Dendrosomal curcumin efficiently suppresses U87MG cells growth with no cytotoxicity related to dendrosome. Additionally, the accumulation of cells in the SubG 1 phase was observed in a time- and dose-dependent manner as well as higher rates of apoptosis after dendrosomal curcumin treatment. Conversely, nonneoplastic cells were not affected by this formulation. Dendrosomal curcumin significantly decreased the relative expression of OCT4A , OCT4B1 , SOX-2 , and Nanog along with noticeable overexpression of miR-145 as the upstream regulator. This suggests that dendrosomal curcumin reduces the proliferation of U87MG cells through the downregulation of OCT4 (octamer binding protein 4) variants and SOX-2 (SRY [sex determining region Y]-box 2) in an miR-145 -dependent manner.

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“…1,2 Glioblastoma is characterized by diffuse infiltration into the brain parenchyma, robust angiogenesis, and poor response to treatment with conventional radiation and chemotherapy. 3 Moreover, most cases of glioblastomas are characterized as primary (de novo) glioblastomas, which develop rapidly without obvious clinical or histological signs of premalignant lesions.…”

Section: Introductionmentioning

confidence: 99%

Itraconazole suppresses the growth of glioblastoma through induction of autophagy

et al. 2014

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Glioblastoma: Therapeutic challenges, what lies ahead

Cited by 105 publications

References 128 publications

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells

Itraconazole suppresses the growth of glioblastoma through induction of autophagy

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