Temozolomide Preferentially Depletes Cancer Stem Cells in Glioblastoma

Beier, Dagmar; Röhrl, Stefanie; Pillai, Deepu R.; Schwarz, Stefanie; Kunz-Schughart, Leoni A.; Leukel, Petra; Proescholdt, Martin; Brawanski, Alexander; Bogdahn, Ulrich; Trampe-Kieslich, Ariane; Giebel, Bernd; Wischhusen, Jörg; Reifenberger, Guido; Hau, Peter; Beier, Christoph P.

doi:10.1158/0008-5472.can-07-6878

Cited by 258 publications

(218 citation statements)

References 44 publications

Supporting

Mentioning

197

Contrasting

Unclassified

Order By: Relevance

“…The reduced amount of stemness positive cells may be a reflection of the reduction of CSCs due to the presence of serum. An additional indication that the tumor spheres observed in our culture conditions harbor bona fide CSCs is the observation that temozolomide, at a sub-toxic concentration of 5 μM, reduced the formation of spheres by 50% (data not shown), similar to the reduction found in primary glioblastoma tumors cultivated with defined factors [10].…”

Section: Atp Reduces Sphere Formationsupporting

confidence: 74%

See 1 more Smart Citation

Extracellular ATP reduces tumor sphere growth and cancer stem cell population in glioblastoma cells

Ledur

Villodre

Paulus

et al. 2011

Purinergic Signalling

View full text Add to dashboard Cite

Glioblastoma is the most aggressive tumor in the CNS and is characterized by having a cancer stem cell (CSC) subpopulation essential for tumor survival. The purinergic system plays an important role in glioma growth, since adenosine triphosphate (ATP) can induce proliferation of glioma cells, and alteration in extracellular ATP degradation by the use of exogenous nucleotidases dramatically alters the size of gliomas in rats. The aim of this work was to characterize the effect of the purinergic system on glioma CSCs. Human U87 glioma cultures presented tumor spheres that express the markers of glioma cancer stem cells CD133, Oct-4, and Nanog. Messenger RNA of several purinergic receptors were differently expressed in spheres when compared to a cell monolayer not containing spheres. Treatment of human gliomas U87 or U343 as well as rat C6 gliomas with 100 μM of ATP reduced the number of tumor spheres when grown in neural stem cell medium supplemented with epidermal growth factor and basic fibroblast growth factor. Moreover, ATP caused a decline in the number of spheres observed in culture in a dose-dependent manner. ATP also reduces the expression of Nanog, as determined by flow cytometry, as well as CD133 and Oct-4, as analyzed by flow cytometry and RT-PCR in U87 cells. The differential expression of purinergic receptor in tumor spheres when compared to adherent cells and the effect of ATP in reducing tumor spheres suggest that the purinergic system affects CSC biology and that ATP may be a potential agonist for differentiation therapy.

show abstract

Section: Atp Reduces Sphere Formationsupporting

confidence: 74%

“…Treatment with some of these agents increased the proportion of CSCs, which may be an explanation for more aggressive recurrence [7]. On the other hand, preferential elimination of CSC population may be a part of the effectiveness of temozolomide, the most effective pharmacologic agent used in glioma treatment [10].…”

Section: Introductionmentioning

confidence: 99%

Extracellular ATP reduces tumor sphere growth and cancer stem cell population in glioblastoma cells

Ledur

Villodre

Paulus

et al. 2011

Purinergic Signalling

View full text Add to dashboard Cite

show abstract

“…In the range of concentrations tested, CGP-2 is more active than temozolomide. In accordance with previous work by Beier and colleagues (45), the intended clinical doses of temozolomide (50 mmol/L in plasma and 10 mmol/L in cerebrospinal fluid; refs. 36, 37) are not sufficient to prevent proliferation.…”

Section: Discussionsupporting

confidence: 67%

Selective Release of a Cyclopamine Glucuronide Prodrug toward Stem-like Cancer Cell Inhibition in Glioblastoma

Balbous

Renoux

Cortes

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Recent data suggest that inhibition of the Hedgehog pathway could be a therapeutic target for glioblastoma. Alkaloid cyclopamine inhibits Hedgehog signaling, depleting stem-like cancer cells derived from glioblastoma. However, this compound is toxic for somatic stem cells, preventing its use for clinical applications. In this study, we tested a derivatization product of cyclopamine in the form of cyclopamine glucuronide prodrug (CGP-2). This compound was used in vitro and in vivo toward glioblastoma-initiating cells (GIC). Results obtained in vitro indicate that CGP-2 is active only in the presence of b-glucuronidase, an enzyme detected in high levels in necrotic areas of glioblastomas. CGP-2 decreased proliferation and inhibited the self-renewal of all GIC lines tested. Hedgehog pathway blockade by 10 mmol/L of CGP-2 induced a 99% inhibition of clonogenicity on GICs, similar to cyclopamine treatment. Combination of CGP-2 with radiation decreased clonogenic survival in all GIC lines compared with CGP-2 alone. In a subcutaneous glioblastoma xenograft model, a two-week CGP-2 treatment prevented tumor growth with 75% inhibition at 8 weeks, and this inhibition was still significant after 14 weeks. Unlike cyclopamine, CGP-2 had no detectable toxic effects in intestinal crypts. Our study suggests that inhibition of the Hedgehog pathway with CGP-2 is more effective than conventional temozolomide adjuvant, with much lower concentrations, and seems to be an effective therapeutic strategy for targeting GICs. Mol Cancer Ther; 13(9); 2159-69. Ó2014 AACR.

show abstract

“…In a genetically engineered glioma mouse model, TMZ treatment increased the side population (SP), a potential measure of cancer stem cells (Bleau et al, 2009). Although TMZ can eliminate MGMT-negative GSCs (Beier et al, 2008), TMZ does not inhibit self-renewal of GSCs with normal levels of MGMT (Clement et al, 2007). Several other potential mechanisms underlying the drug resistance of GSCs have also been reported.…”

Section: Cancer Stem Cells and Therapeutic Resistance Of Glioblastomamentioning

confidence: 99%

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

et al. 2010

View full text Add to dashboard Cite

Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.

show abstract

Temozolomide Preferentially Depletes Cancer Stem Cells in Glioblastoma

Cited by 258 publications

References 44 publications

Extracellular ATP reduces tumor sphere growth and cancer stem cell population in glioblastoma cells

Extracellular ATP reduces tumor sphere growth and cancer stem cell population in glioblastoma cells

Selective Release of a Cyclopamine Glucuronide Prodrug toward Stem-like Cancer Cell Inhibition in Glioblastoma

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

Contact Info

Product

Resources

About