Search results for: NVP-HSP-990 Mechanisms: Hsp90 inhibitor
#28255900 
2017/03/02
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Re-examining HSPC1 inhibitors.
HSPC1 is a critical protein in cancer development and progression, including colorectal cancer (CRC). However, clinical trial data reporting the effectiveness of HSPC1 inhibitors on several cancer types has not been as successful as predicted. Furthermore, some N-terminal inhibitors appear to be much more successful than others despite similar underlying mechanisms. This study involved the application of three N-terminal HSPC1 inhibitors, 17-DMAG, NVP-AUY922 and NVP-HSP990 on CRC cells. The effects on client protein levels over time were examined. HSPC1 inhibitors were also applied in combination with chemotherapeutic agents commonly used in CRC treatment (5-fluorouracil, oxaliplatin and irinotecan). As HSPA1A and HSPB1 have anti-apoptotic activity, gene-silencing techniques were employed to investigate the significance of these proteins in HSPC1 inhibitor and chemotherapeutic agent resistance. When comparing the action of the three HSPC1 inhibitors, there are distinct differences in the time course of important client protein degradation events. The differences between HSPC1 inhibitors were also reflected in combination treatment-17-DMAG was more effective compared with NVP-AUY922 in potentiating the cytotoxic effects of 5-fluorouracil, oxaliplatin and irinotecan. This study concludes that there are distinct differences between N-terminal HSPC1 inhibitors, despite their common mode of action. Although treatment with each of the inhibitors results in significant induction of the anti-apoptotic proteins HSPA1A and HSPB1, sensitivity to HSPC1 inhibitors is not improved by gene silencing of HSPA1A or HSPB1. HSPC1 inhibitors potentiate the cytotoxic effects of chemotherapeutic agents in CRC, and this approach is readily available to enter clinical trials. From a translational point of view, there may be great variability in sensitivity to the inhibitors between individual patients.Sheah Lin Lee, Nina Claire Dempsey-Hibbert, Dale Vimalachandran, Terence David Wardle, Paul A Sutton, John H H Williams
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#23492364 2013/03/14
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Novel HSP90 inhibitor NVP-HSP990 targets cell-cycle regulators to ablate Olig2-positive glioma tumor-initiating cells.
Genetic heterogeneity and signaling alterations diminish the effectiveness of single-agent therapies in glioblastoma multiforme (GBM). HSP90 is a molecular chaperone for several signaling proteins that are deregulated in glioma cells. Thus, HSP90 inhibition may offer an approach to coordinately correct multiple signaling pathways as a strategy for GBM therapy. In this study, we evaluated the effects of a novel HSP90 inhibitor, NVP-HSP990, in glioma tumor-initiating cell (GIC) populations, which are strongly implicated in the root pathobiology of GBM. In GIC cultures, NVP-HSP990 elicited a dose-dependent growth inhibition with IC50 values in the low nanomolar range. Two GIC subgroups with different responses were observed with an Olig2-expressing subset relatively more sensitive to treatment. We also showed that Olig2 is a functional marker associated with cell proliferation and response to NVP-HSP990, as NVP-HSP990 attenuated cell proliferation in Olig2-high GIC lines. In addition, NVP-HSP990 disrupted cell-cycle control mechanism by decreasing CDK2 and CDK4 and elevating apoptosis-related molecules. Mechanistic investigations revealed molecular interactions between CDK2/CDK4 and Olig2. Inhibition of CDK2/CDK4 activity disrupted Olig2-CDK2/CDK4 interactions and attenuated Olig2 protein stability. In vivo evaluation showed a relative prolongation of median survival in an intracranial model of GIC growth. Our results suggest that GBM characterized by high-expressing Olig2 GIC may exhibit greater sensitivity to NVP-HSP990 treatment, establishing a foundation for further investigation of the role of HSP90 signaling in GBM.Jun Fu, Dimpy Koul, Jun Yao, Shuzhen Wang, Ying Yuan, Howard Colman, Erik P Sulman, Frederick F Lang, W K Alfred Yung
1300 related Products with: Novel HSP90 inhibitor NVP-HSP990 targets cell-cycle regulators to ablate Olig2-positive glioma tumor-initiating cells.
2 Pieces/Box1.5 x 10^6 cells3 inhibitorsOne Vial: 5 X 10^6 Cells5mg1.5x10(6) cells2 Pieces/Boxcultured cells (100 ml)1 mg1 kit
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#21859842 2011/08/22
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Targeting HSP 90 induces apoptosis and inhibits critical survival and proliferation pathways in multiple myeloma.
The second most commonly diagnosed hematologic malignancy, multiple myeloma, affects predominantly older patients (>60s) and is characterized by paraprotein in the serum or urine. Clinical manifestations include anemia, hypercalcaemia, progressive renal impairment, and osteolytic bone destruction. Despite promising new therapies, multiple myeloma eventually relapses in almost all patients. HSP are ubiquitous and highly conserved in prokaryotes and eukaryote organisms. Exposure to a broad range of stimuli results in increased HSP protein expression. These chaperone proteins are involved in protein transportation, prevent protein aggregation, and ensure correct folding of nascent and stress-accumulated misfolded proteins. In cancer, HSP expression is dysregulated, resulting in elevated expression, which promotes cancer by preventing programmed cell death and supporting autonomous cells growth, ultimately leading to resistance to heat, chemotherapy, and other stresses. Client proteins of HSP90 such as AKT, p53, MEK, STAT3, and Bcr-Abl are vital in tumor progression, including multiple myeloma, and their maturation and stability is dependent on HSP90. Therefore, inhibition of HSP90 via a HSP90 inhibitor (such as NVP-HSP990) should interrupt multiple signaling pathways essential for oncogenesis and growth in multiple myeloma. Our study showed that NVP-HSP990 triggered apoptosis in a panel of human multiple myeloma cells, induced cell-cycle arrest, PARP cleavage, downregulation of client proteins, the inability to reactivate phospho-STAT3 following exogenous IL-6 stimulation, and it synergized with azacytidine and bortezomib in cell lines and primary multiple myeloma samples. The mechanism of HSP90 inhibition in multiple myeloma warrants further evaluation.Tiffany Khong, Andrew Spencer