Inhibition of Sonic Hedgehog and Notch Pathways Enhances Sensitivity of CD133+ Glioma Stem Cells to Temozolomide Therapy

Ulasov, Ilya V.; Nandi, Sumon; Dey, Mahua; Sonabend, Adam M.; Lesniak, Maciej S.

doi:10.2119/molmed.2010.00062

Cited by 164 publications

(125 citation statements)

References 41 publications

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“…Many studies have demonstrated that chemical intervention or downregulation of these signalling pathways increased the therapy sensitivity of CSCs in various cancers [83][84][85]. Ulasov et al reported that CD133þ glioblastoma stem cells increase the expression of the genes involved in Notch and Hedgehog pathways, making the glioblastoma insensitive to chemotherapy (temozolomide) [83].…”

Section: Signalling Pathways Involved In Therapy Resistance Of Cscmentioning

confidence: 99%

“…Ulasov et al reported that CD133þ glioblastoma stem cells increase the expression of the genes involved in Notch and Hedgehog pathways, making the glioblastoma insensitive to chemotherapy (temozolomide) [83]. Also, inhibition of components of theses pathways with gamma-secretase inhibitors and cyclopamine, respectively, increased the sensitivity of CSCs to the treatment [83]. In addition, treatment of non-small cell lung cancer stem cells (CD133þ cell) with gamma-secretase inhibitors or Notch1 shRNA increased their sensitivity against doxorubicin and paclitaxel [84].…”

Section: Signalling Pathways Involved In Therapy Resistance Of Cscmentioning

confidence: 99%

See 1 more Smart Citation

Translational potential of cancer stem cells: A review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment

Islam

Gopalan

Smith³

2015

Experimental Cell Research

112

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Section: Signalling Pathways Involved In Therapy Resistance Of Cscmentioning

confidence: 99%

Section: Signalling Pathways Involved In Therapy Resistance Of Cscmentioning

confidence: 99%

Translational potential of cancer stem cells: A review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment

Islam

Gopalan

Smith³

2015

Experimental Cell Research

112

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“…Specific labeling densities of the analyzed sections from each tumor were summed in order to obtain an integrated fluorescence density in the tumor. Data in histograms of b-d were analyzed with the Kruskal-Wallis test (ns p>0.05, **p<0.01, ***p<0.001) and are represented as mean±standard deviation (SD) cyclopamine improves the sensitivity of GSCs to TMZ, while stimulation of the Hh pathway enhances the resistance to TMZ (Bar et al 2007;Ulasov et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Cytotoxic Properties of a Cyclopamine Glucuronide Prodrug in Rat Glioblastoma Cells and Tumors

et al. 2014

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Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Activation of the developmental hedgehog (Hh) pathway is observed in GBM, particularly in the so-called glioma stem cells (GSCs). An inhibitor of this pathway is the steroidal alkaloid cyclopamine, an antagonist of the Hh coreceptor Smoothened (SMO). To limit the toxicity of cyclopamine toward Hh-dependent non-tumor cells, our group previously reported the synthesis of a prodrug (called 1b), designed to deliver cyclopamine in the presence of β-glucuronidase, an enzyme found in the necrotic area of GBM. Here, we aimed to analyze the in vitro, ex vivo, and in vivo cytotoxic properties of this prodrug in the C6 rat GBM cells. In the presence of β-glucuronidase, the activated prodrug 1b was toxic and downregulated expression of Gli1, a Hh target gene, in C6 cells and C6-GSCs, but not in normal rat astrocytes in which the Hh pathway is weakly activated. In the absence of β-glucuronidase, prodrug 1b displayed no obvious toxicity toward rat brain tissue explants while cyclopamine clearly affected brain tissue viability. When administered to rats bearing fluorescent C6-derived GBM, the prodrug 1b reduced the tumor density more efficiently than cyclopamine. Prodrug 1b thus appears as a promising concept to optimize confinement of cyclopamine cytotoxicity within the tumors, with more limited effects in the surrounding normal brain tissue.

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“…Topical findings have shown BTSCs interacting with astrocytes and up-regulate various survival genes, confering the BTSCs chemoresistant . A recent study found that glioma cells expressing CD133 were more resistant to temozolomide than unsorted glioma cells and showed enhanced transcriptional activity of the Notch and Sonic hedgehog pathways post-treatment in vitro (Ulasov, Nandi et al 2011). Inhibition of Notch and Sonic signaling by co-administration of γ-secretase inhibitor-1 and cyclopamine with temozolomide resulted in significantly increased cell death in the CD133+ subpopulation in vitro, suggesting a potential additive benefit of combination therapy that should be further explored (Ulasov, Nandi et al 2011).…”

Section: Chemotherapymentioning

confidence: 99%

Brain Tumor Treatment: 2017 Update

Chakraborty¹,

Han²,

Faltas³

et al. 2018

CCO

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Malignant brain tumors are a heterogeneous group of diseases arising from different cell types that affect both adults and children. The high recurrence rate of malignant brain tumors typically is due to reappearance of focal masses, indicating that a sub population of tumor cells are insensitive to current therapies and may be responsible for reinitiating tumor growth. It is generally agreed that the resistant tumor cells are comprised of cancer stem cells or tumor-initiating cells. While brain tumor stem cells (BTSCs) were first isolated within the last decade, much of the early research has been focused on identifying the BTSC markers and therapeutic targets. The challenge however, is to translate this knowledge to therapeutics. In the current review, we survey the remedial strategies to target BTSCs, which includes diagnostic, pharmacologic, immunologic, viral, and post-transcriptional approaches.

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Inhibition of Sonic Hedgehog and Notch Pathways Enhances Sensitivity of CD133+ Glioma Stem Cells to Temozolomide Therapy

Cited by 164 publications

References 41 publications

Translational potential of cancer stem cells: A review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment

Translational potential of cancer stem cells: A review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment

Evaluation of Cytotoxic Properties of a Cyclopamine Glucuronide Prodrug in Rat Glioblastoma Cells and Tumors

Brain Tumor Treatment: 2017 Update

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