Multifunctional Magnetic Nanoplatform Eliminates Cancer Stem Cells via Inhibiting the Secretion of Extracellular Heat Shock Protein 90

2019 ◽  
Vol 8 (13) ◽  
pp. 1900160 ◽  
Author(s):  
Yajing Liu ◽  
Xiaomin Suo ◽  
Haotong Peng ◽  
Weixiao Yan ◽  
Hongjuan Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Heat Shock ◽  
Cancer Stem Cells ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90

scholarly journals Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I–induced leukemia and suppresses leukemic stem cells

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 678-685 ◽  
Author(s):  
Cong Peng ◽  
Julia Brain ◽  
Yiguo Hu ◽  
Ami Goodrich ◽  
Linghong Kong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Myelogenous Leukemia ◽  
Leukemia Stem Cells

Abstract Development of kinase domain mutations is a major drug-resistance mechanism for tyrosine kinase inhibitors (TKIs) in cancer therapy. A particularly challenging example is found in Philadelphia chromosome–positive chronic myelogenous leukemia (CML) where all available kinase inhibitors in clinic are ineffective against the BCR-ABL mutant, T315I. As an alternative approach to kinase inhibition, an orally administered heat shock protein 90 (Hsp90) inhibitor, IPI-504, was evaluated in a murine model of CML. Treatment with IPI-504 resulted in BCR-ABL protein degradation, decreased numbers of leukemia stem cells, and prolonged survival of leukemic mice bearing the T315I mutation. Hsp90 inhibition more potently suppressed T315I-expressing leukemia clones relative to the wild-type (WT) clones in mice. Combination treatment with IPI-504 and imatinib was more effective than either treatment alone in prolonging survival of mice simultaneously bearing both WT and T315I leukemic cells. These results provide a rationale for use of an Hsp90 inhibitor as a first-line treatment in CML by inhibiting leukemia stem cells and preventing the emergence of imatinib-resistant clones in patients. Rather than inhibiting kinase activity, elimination of mutant kinases provides a new therapeutic strategy for treating BCR-ABL–induced leukemia as well as other cancers resistant to treatment with tyrosine kinase inhibitors.

scholarly journals A Brain Penetrating Heat-Shock Protein 90 Inhibitor NXD30001 Inhibits Glioblastoma as a Monotherapy or in Combination With Radiation

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Hao Chen ◽  
Jialiang Wang ◽  
Hengli Tian
Keyword(s):  
Stem Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Median Survival ◽  
Therapeutic Potential ◽  
Heat Shock Protein 90 ◽  
Tumor Bearing ◽  
Client Proteins

Abstract INTRODUCTION It has been increasingly recognized that glioblastoma multiforme (GBM) is a highly heterogeneous disease, which is initiated and sustained by molecular alterations in an array of signal transduction pathways. Heat-shock protein 90 (Hsp90) is a molecular chaperone to be critically implicated in folding and activation of a diverse group of client proteins, many of which are key regulators of important glioblastoma biology. METHODS To determine the therapeutic potential of targeting Hsp90 in glioblastoma, we assessed the anti-neoplastic efficacy of NXD30001, a brain-penetrating Hsp90 inhibitor as a monotherapy or in combination with radiation, both in Vitro and in Vivo. RESULTS Our results demonstrated that NXD30001 potently inhibited neurosphere formation, growth and survival of CD133 + glioblastoma stem cells (GSCs) with the half maximal inhibitory concentrations (IC50) at low nanomolar concentrations. At suboptimal concentrations, inhibition of Hsp90 did not exert cytotoxic activity but rather increased radiosensitivity in GSCs. CD133- GBM cells were less sensitive and not radiosensitized by NXD30001. In lines with its cytotoxic and radiosensitizing effects, NXD30001 dose-dependently decreased phosphorylation protein levels of multiple Hsp90 client proteins, including those playing key roles in GSCs, such as EGFR, Akt, c-Myc, and Notch1. In addition, combining NXD30001 with radiation could impair DNA damage response and ER stress response to induce apoptosis of GSCs. Treatment of orthotopic glioblastoma tumors with NXD30001 extended median survival of tumor-bearing mice by approximately 20% (treated 37 days vs vehicle 31 d, P = .0026). Radiation alone increased median survival of tumor-bearing mice from 31 to 38 d, combination with NXD30001 further extended survival to 43 d (P = .0089). CONCLUSION Our results suggest that GBM stem cells (CD133+) are more sensitive to NXD30001 than non-stem GBM cells (CD133-). Furthermore, combination NXD30001 with radiation significantly inhibits GBM progression than use it as a monotherapy by targeting GSCs.

scholarly journals e0204 Heat shock protein 90 enhances rat mesenchymal stem cells migration via PI3KAkt and ERK12 pathways

Heart ◽  
2010 ◽  
Vol 96 (Suppl 3) ◽  
pp. A65-A66
Author(s):  
G. Feng ◽  
H. Xinyang ◽  
X. Xiaojie ◽  
X. Qiyuan ◽  
W. Yaping ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90

scholarly journals Potential role of heat shock protein 90 in regulation of hyperthermia-driven differentiation of neural stem cells

2019 ◽  
Author(s):  
Lei Wang ◽  
Yi Zhuo ◽  
Zhengwen He ◽  
Ying Xia ◽  
Ming Lu
Keyword(s):  
Stem Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Neural Stem Cells ◽  
Time Window ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Control Group ◽  
Transcriptional Level ◽  
Hyperthermic Treatment

AbstractObjectiveOur previous studies indicated that hyperthermia may play a role in differentiation of neural stem cells and that hypoxia inducible factor-1(HIF-1) was critical in this process. Heat shock protein 90 (Hsp90) is one of the most common heat-related proteins and involved in HIF-1 expression by regulating its activity and stabilization. Here, we hypothesized that HSP90 may be involved in regulation of hyperthermia-driven differentiation of neural stem cells(NSCs). We also investigated whether the HSP90 activity exert its regulatory action via HIF-1 pathway and the transcriptional level of the target genes of HIF-1.MethodThe cultured NSCs were divided into three groups: an hyperthermic treatment group(40NSC) which NSCs was induced under 40°C temperature; a control group(37NSC) which NSCs was induced under 37°C temperature; an hyperthermic treatment and HSP90-inhibited group(40NSC+GA) which NSCs was induced with 0.5μM HSP90 inhibitor Geldanamycin(GA) under 40°C temperature. We examined cells HSPa and HIF-1a expression during a time window of 5 days(12h, 1d, 3d, 5d) post-differentiation. The expression HSPα, HIF-1α, VEGF (vascular endothelial growth factor) and erythmpoietin(EPO) of during a time window was evaluated by RT-qPCR. The proportion of Tuj-1 positive differentiated cells were observed by flow cytometry.ResultHyperthermia promoted neuronal differentiation of NSC, and this effect could be blocked by HSP90 inhibitor GA. We observed the up-regulation of HSP90 during hyperthermia treatment, and that the protein levels of HIF-1α changed depending of the GA treatment. GA could not inhibited HSP90α expression but suppressed HSP activity and decreased the expression HIF-1α protein. Inhibition of HIF-1α expression by GA could consequently affect expression of its targeted genes such as VEGF and EPO.ConclusionHyperthermia promote differentiation of NSCs into neurons. HSP90 involved in the regulation of hyperthermia-driven differentiation of NSC, and the mechanism is related to HIF-1α and its downstream gene activation.

scholarly journals Heat Shock Protein 90 Inhibition in Kasumi‐1 Leukemic Stem Cells

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Matthew Jeremy Rosolen ◽  
MacKinzie D. Smith ◽  
Nickolas A. Bacon ◽  
Vincent Sollars
Keyword(s):  
Stem Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Leukemic Stem Cells

scholarly journals e0201 Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivationinduced apoptosis via PI3KAkt and ERK12 pathways

Heart ◽  
2010 ◽  
Vol 96 (Suppl 3) ◽  
pp. A64-A65
Author(s):  
G. Feng ◽  
H. Xinyang ◽  
X. Xiaojie ◽  
X. Qiyuan ◽  
W. Yaping ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90
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