Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells

Sauvageot, Claire; Weatherbee, Jessica L.; Kesari, Santosh; Winters, Susan Elizabeth; Barnes, Jack A.; DellaGatta, Jamie L.; Ramakrishna, Naren; Stiles, Charles D.; Kung, Andrew L.; Kieran, Mark W.; Wen, Patrick Y.

doi:10.1215/15228517-2008-060

Cited by 122 publications

(117 citation statements)

References 46 publications

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…It has been shown that Hsp90 inhibition could sensitize chemoresistant CSC-like cells to DNA-damaging agents (23,24). We also reported that Hsp90 inhibition resulted in destabilizing MYCN and MYC in NB cells (25).…”

Section: Short-term Treatments With Epigenetic Modifiers Enhance the mentioning

confidence: 86%

Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

Ikegaki

Shimada

Fox

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cancer stem cells (CSCs) are plastic in nature, a characteristic that hampers cancer therapeutics. Neuroblastoma (NB) is a pediatric tumor of neural crest origin, and half of the cases are highly aggressive. By treating NB cell lines [SKNAS, SKNBE(2)C, CHP134, and SY5Y] with epigenetic modifiers for a short time, followed by sphere-forming culture conditions, we have established stem cell-like NB cells that are phenotypically stable for more than a year. These cells are characterized by their high expression of stemness factors, stem cell markers, and open chromatin structure. We referred to these cells as induced CSCs (iCSCs). SKNAS iCSC and SKNBE(2)C iCSC clones (as few as 100 cells) injected s.c. into SCID/Beige mice formed tumors, and in one case, SKNBE(2)C iCSCs metastasized to the adrenal gland, suggesting their increased metastatic potential. SKNAS iCSC xenografts showed the histologic appearance of totally undifferentiated large-cell NBs (LCNs), the most aggressive and deadly form of NB in humans. Immunohistochemical analyses showed that SKNAS iCSC xenografts expressed high levels of the stem cell marker CXCR4, whereas the SKNAS monolayer cell xenografts did not. The patterns of CXCR4 and MYC expression in SKNAS iCSC xenografts resembled those in the LCNs. The xenografts established from the NB iCSCs shared two common features: the LCN phenotype and high-level MYC/MYCN expression. These observations suggest both that NB cells with large and vesicular nuclei, representing their open chromatin structure, are indicative of stem cell-like tumor cells and that epigenetic changes may have contributed to the development of these most malignant NB cells.tumor initiating cells | prominent nucleoli N euroblastoma (NB) is the most common extracranial pediatric malignancy. Although some NBs are easily treatable, nearly 50% of the tumors exhibit aggressive behavior. The International Neuroblastoma Risk Group Classification is used to classify NB at diagnosis (1). High-risk NBs are associated with older age, advanced stages, unfavorable histologic features, widespread tumor dissemination, and poor long-term survival (1). Current treatment for these NBs includes high-dose chemotherapy or myeloablative cytotoxic therapy with autologous hematopoietic stem cell transplantation (2). However, late relapse is often seen despite achieving complete clinical remission. A subset of high-risk NBs, which is refractory to current frontline therapy designed for high-risk NB, is termed ultra-high-risk NB (3, 4).NB is histopathologically defined as neuroblastic tumors with less than 50% Schwannian stromal components. On the basis of the degree of neuronal differentiation, NB is further divided into undifferentiated (UD), poorly differentiated, and differentiating subtypes (5, 6). A unique histological subset of NBs within the UD and poorly differentiated subtypes has also been identified (7,8). These tumors are uniformly composed of large cells with sharply outlined nuclear membranes and one to four prominent nucleoli and are referred...

show abstract

Section: Short-term Treatments With Epigenetic Modifiers Enhance the mentioning

confidence: 86%

Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

Ikegaki

Shimada

Fox

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Interestingly, 17-AAG inhibited the growth of intracranial tumors and synergized with radiation both in tissue culture and in intracranial tumors. On the contrary, 17-AAG did not synergize with temozolomide in any of glioma models (138). The response of glioblastoma cells to combination of Hsp90 inhibitor with other therapy is summarized in Table VI.…”

Section: Combination Of Hsp90 Inhibitor With Second Therapymentioning

confidence: 96%

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

Solárová¹,

Mojžiš²,

Solár³

2014

Int J Oncol

View full text Add to dashboard Cite

Abstract. Hsp90 is a molecular chaperone that maintains the structural and functional integrity of various client proteins involved in signaling and many other functions of cancer cells. The natural inhibitors, ansamycins influence the Hsp90 chaperone function by preventing its binding to client proteins and resulting in their proteasomal degradation. Nand C-terminal inhibitors of Hsp90 and their analogues are widely tested as potential anticancer agents in vitro, in vivo as well as in clinical trials. It seems that Hsp90 competitive inhibitors target different tumor types at nanomolar concentrations and might have therapeutic benefit. On the contrary, some Hsp90 inhibitors increased toxicity and resistance of cancer cells induced by heat shock response, and through the interaction of survival signals, that occured as side effects of treatments, could be very effectively limited via combination of therapies. The aim of our review was to collect the data from experimental and clinical trials where Hsp90 inhibitor was combined with other therapies in order to prevent resistance as well as to potentiate the cytotoxic and/or antiproliferative effects.

show abstract

“…Recently, it has also been shown that inhibition of the Notch signaling pathway by the γ-secretase inhibitor or Notch shRNA renders GSCs more sensitive to radiation , suggesting that Notch pathway may serve as another potential target for reducing GBM radioresistance. In addition, recent studies suggested that targeting SirT1 expression or HSP90 activity can also attenuate radioresistance of GSC population (Chang et al, 2009;Sauvageot et al, 2009). It seems that multiple molecular mechanisms regulate GSC radioresistance, perhaps with intertumoral variation.…”

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

Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells

Cited by 122 publications

References 46 publications

Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

Contact Info

Product

Resources

About