Advances in the Treatment of Malignant Gliomas

Khasraw, Mustafa; Lassman, Andrew B.

doi:10.1007/s11912-009-0077-4

Cited by 111 publications

(91 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Glioblastoma multiforme (GBM, WHO IV) is the most common adult intracranial malignancy which is characterized by rapid tumor proliferation and a strong tendency to diffuse and invade surrounding normal brain tissue (1). Despite ongoing improvements in conventional therapeutic regimens, including selective surgical resection and concurrent radiation, the prognosis for glioblastoma patients remains extremely dismal (2).…”

Section: Introductionmentioning

confidence: 99%

Notch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cells

Lin

Xiong²,

Zhang

et al. 2011

Oncol Rep

View full text Add to dashboard Cite

Abstract. Glioblastoma is the most malignant form of adult brain tumor and is associated with a dismal prognosis. Emerging data suggest that Notch signaling participates principally in the formation and malignant progression of glioblastoma. Resveratrol is a terpenoid that exhibits broad pro-apoptotic activity in various types of cancers, including glioblastoma. However, the effects of resveratrol on Notch signaling in glioblastomas have not yet been fully elucidated. We demonstrated that resveratrol strongly suppressed cell growth and induced apoptosis in A172 and T98G glioblastoma cells, which have low active Notch-1 expression and a heterozygous p53 mutation. Our results suggest that resveratrol significantly activates intracellular Notch-1 and restores wild-type p53 expression in a time-dependent manner. Significant de-phosphorylation of Akt, increased Bax expression, decreased Bcl-2 expression and cleavage of caspase-3 were also observed in resveratrol-induced apoptosis in glioblastoma cells. Moreover, simultaneous treatment with resveratrol and a Notch-1 inhibitor (MRK-003) partially attenuated the apoptosis and completely blocked the activation of Notch-1 and the increase in wild-type p53. This suggests that restoration of wild-type p53 expression depends on Notch-1 activation. In addition, the de-phosphorylation of Akt, increased expression of Bax and cleavage of caspase-3 were not fully reversed by MRK-003 treatment, suggesting that p53 restoration is not the only mechanism underlying resveratrol-induced apoptosis. Taken together, we confirmed the anti-proliferative and pro-apoptotic effects of resveratrol on glioblastoma cells and revealed Notch-1 activation-dependent restoration of p53 as an important causative mechanism.

show abstract

Section: Introductionmentioning

confidence: 99%

Notch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cells

Lin

Xiong²,

Zhang

et al. 2011

Oncol Rep

View full text Add to dashboard Cite

show abstract

“…Glioblastoma multiforme (GBM) is the most lethal primary brain tumor [31]. Drug treatments are without notable success for glioblastomas and despite continuous improvement of GMB therapy, usually consisting in surgical tissue resection, the majority of patients do not survive beyond one year after diagnosis of recurrent disease [32].…”

Section: Introductionmentioning

confidence: 99%

Expression of Tumor Suppressors PTEN and TP53 in Isogenic Glioblastoma U-251MG Cells Affects Cellular Mechanical Properties — An AFM-Based Quantitative Investigation

Berquand¹,

Kuhn²,

Holloschi³

et al. 2013

Proc. 20th International Colloquium on Scanning Probe Microscopy

View full text Add to dashboard Cite

Glioblastoma is the most common and malign form of brain cancer that is highly resistant to therapy and particularly hard to cure since the blood-barrier is not very permeable to drugs. Moreover, a surgery is always highly risky. Thus, there is a real need to develop technique enabling accurate identification of potentially tumor cells at an early stage. It is getting well established that cancer cells are usually softer than their normal homologues and Atomic Force Microscopy (AFM) has proven itself over the last decade to be a tool of choice to characterize cells mechanical properties. Among the various AFM techniques, Force Spectroscopy (FS), especially Force Volume (FV) is the most commonly used. In the present study, AFM has been used to successfully characterize malignant and modified less malignant forms of glioblastoma U-251MG isogenic cells, using FV and Peak Force Tapping (PFT), a newly released AFM mode. Although both modes are quantitative and easy to use, PFT appears as the most relevant. Benefits and drawbacks of both techniques are discussed.

show abstract

“…The standard of care for glioblastoma is composed of maximal surgical resection followed by radiotherapy with concomitant and adjuvant chemotherapy [1,2]. Temozolomide is a monofunctional alkylating agent currently used as the first-line chemotherapeutic agent against newly diagnosed glioblastoma and is also a drug of choice for recurrent disease [3,4].…”

Section: Introductionmentioning

confidence: 99%

MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis

et al. 2011

View full text Add to dashboard Cite

Overcoming the resistance of glioblastoma cells against temozolomide, the first-line chemotherapeutic agent of choice for newly diagnosed glioblastoma, is a major therapeutic challenge in the management of this deadly brain tumor. The gene encoding O 6 -methylguanine DNA methyltransferase (MGMT), which removes the methyl group attached by temozolomide, is often silenced by promoter methylation in glioblastoma but is nevertheless expressed in a significant fraction of cases and is therefore regarded as one of the most clinically relevant mechanisms of resistance against temozolomide. However, to date, signaling pathways regulating MGMT in MGMT-expressing glioblastoma cells have been poorly delineated. Here in this study, we provide lines of evidence that the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK)-murine double minute 2 (MDM2)-p53 pathway plays a critical role in the regulation of MGMT expression, using stem-like glioblastoma cells directly derived from patient tumor samples and maintained in the absence of serum, which not only possess stem-like properties but are also known to phenocopy the characteristics of the original tumors from which they are derived. We show that, in stem-like glioblastoma cells, MEK inhibition reduced MDM2 expression and that inhibition of either MEK or MDM2 resulted in p53 activation accompanied by p53-dependent downregulation of MGMT expression. MEK inhibition rendered otherwise resistant stem-like glioblastoma cells sensitive to temozolomide, and combination of MEK inhibitor and temozolomide treatments effectively deprived stem-like glioblastoma cells of their tumorigenic potential. Our findings suggest that targeting of the MEK-ERK-MDM2-p53 pathway in combination with temozolomide could be a novel and promising therapeutic strategy in the treatment of glioblastoma. STEM CELLS

show abstract

Advances in the Treatment of Malignant Gliomas

Cited by 111 publications

References 42 publications

Notch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cells

Notch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cells

Expression of Tumor Suppressors PTEN and TP53 in Isogenic Glioblastoma U-251MG Cells Affects Cellular Mechanical Properties — An AFM-Based Quantitative Investigation

MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis

Contact Info

Product

Resources

About