Brain cancer propagating cells: biology, genetics and targeted therapies

Hadjipanayis, Constantinos; Meir, Erwin G. Van

doi:10.1016/j.molmed.2009.09.003

Cited by 109 publications

(88 citation statements)

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“…Glioblastoma (GBM) is the most frequent type of glioma, comprising almost 50% of all diagnosed gliomas (1)(2)(3)(4). The median survival of GBM patients remained between 9 and 12 months until 2004 when patients started chemotherapy with temozolamide (TMZ).…”

Section: Introductionmentioning

confidence: 99%

Effect of temozolomide on the U-118 glioma cell line

et al. 2011

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Abstract. Glioblastomas (GBM) are the most lethal subtype of astrocytomas, with a mean patient survival rate of 12 months after diagnosis. The gold standard treatment of GBM, which includes surgery followed by the combination of radiotherapy and chemotherapy with temozolomide (TMZ), increases the survival rate to 14.6 months. The success of TMZ appears to be limited by the occurrence of chemoresistance that allows glioma cells to escape from death signaling pathways. However, the mechanism of TMZ action is yet to be clarified although some controversial results have been reported. Therefore, our aim was to evaluate the occurrence of apoptosis and autophagy in glioma cells treated with TMZ and to correlate TMZ action with the survival pathways Pi3K/ Akt and ERK1/2 MAP kinase. Cell proliferation was evaluated by incorporation of bromodeoxyuridine. Apoptosis was studied by flow cytometry as well as by fluorescence confocal microscopy in order to evaluate the sub G0/G1 percentage of cells and chromatin condensation. The expression of the autophagy-associated protein, LC3, as well as Akt and ERK1/2 was performed by Western blotting. In TMZ-treated GBM cells the expression of LC3, the autophagy-associated protein was increased and only a reduced percentage of cells underwent apoptosis. In addition, we showed that the phosphorylation status of Pi3K/Akt and ERK1/2 MAP kinase was maintained during the treatment with TMZ, suggesting that glioma cells escape from TMZ-induced cell death due to these signaling pathways. The chemoresistance of U-118 cells to TMZ was partially eradicated when cells were simultaneously treated with specific inhibitors of Pi3K/Akt and ERK1/2 MAP kinase signaling pathways and TMZ. Therefore, we hypothesized that in order to induce glioma cell death it is essential to evaluate the activation of the survival pathways and establish a combined therapy using TMZ and inhibitors of those signaling pathways.

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Section: Introductionmentioning

confidence: 99%

Effect of temozolomide on the U-118 glioma cell line

et al. 2011

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“…6,8 This highlights the importance of designing new classes of agents that specifically target GSCs. Multiple intracellular signaling pathways regulate proliferation, differentiation, survival, and chemoresistance of GSCs, 9 which limits the value of smallmolecule inhibitors of individual pathways in the treatment of malignant gliomas. 10,11 This encourages the search for novel therapeutic targets that lie upstream of signal propagation and have a strong impact on the fate of GSCs.…”

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confidence: 99%

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

et al. 2012

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Drug treatment of malignant gliomas is limited by the intrinsic resistance of glioma stem cells (GSCs) to chemotherapy. GSCs isolated from human glioblastoma multiforme (GBM) expressed metabotropic glutamate receptors (mGlu3 receptors). The DNAalkylating agent, temozolomide, killed GSCs only if mGlu3 receptors were knocked down or pharmacologically inhibited. In contrast, mGlu3 receptor blockade did not affect the action of paclitaxel, etoposide, cis-platinum, and irinotecan. mGlu3 receptor blockade enabled temozolomide toxicity by inhibiting a phosphatidylinositol-3-kinase/nuclear factor-jB pathway that supports the expression of O 6 -methylguanine-DNA methyltransferase (MGMT), an enzyme that confers resistance against DNAalkylating agents. In mice implanted with GSCs into the brain, temozolomide combined with mGlu3 receptor blockade substantially reduced tumor growth. Finally, 87 patients with GBM undergoing surgery followed by adjuvant chemotherapy with temozolomide survived for longer time if tumor cells expressed low levels of mGlu3 receptors. In addition, the methylation state of the MGMT gene promoter in tumor extracts influenced survival only in those patients with low expression of mGlu3 receptors in the tumor. These data encourage the use of mGlu3 receptor antagonists as add-on drugs in the treatment of GBM, and suggest that the transcript of mGlu3 receptors should be measured in tumor specimens for a correct prediction of patients' survival in response to temozolomide treatment.

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“…As HGF, its receptor c-met has been implicated in the genesis, malignant progression, and chemo/radioresistance of multiple human malignancies, including gliomas (Peruzzi et al, 2006;Carapancea et al, 2009;Hadjipanayis et al, 2009aHadjipanayis et al, , 2009b. Experimental studies using transient expression of anti-SF/HGF and anti-c-met U1snRNA/ribozymes suppress SF/HGF and c-met expression, c-met receptor activation, tumor cell migration, and anchorage-independent colony formation in vitro.…”

Section: Hepatocyte Growth Factor and Malignant Gliomasmentioning

confidence: 99%