scholarly journals A Novel Mechanism for Cross-Adaptation between Heat and Altitude Acclimation: The Role of Heat Shock Protein 90

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Roy M. Salgado ◽  
Ailish C. White ◽  
Suzanne M. Schneider ◽  
Christine M. Mermier
Keyword(s):  
Heat Stress ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Heat Acclimation ◽  
Functional Roles ◽  
Hypoxic Environment ◽  
Client Proteins

Heat shock protein 90 (HSP90) is a member of a family of molecular chaperone proteins which can be upregulated by various stressors including heat stress leading to increases in HSP90 protein expression. Its primary functions include (1) renaturing and denaturing of damaged proteins caused by heat stress and (2) interacting with client proteins to induce cell signaling for gene expression. The latter function is of interest because, in cancer cells, HSP90 has been reported to interact with the transcription hypoxic-inducible factor 1α (HIF1α). In a normoxic environment, HIF1α is degraded and therefore has limited physiological function. In contrast, in a hypoxic environment, stabilized HIF1α acts to promote erythropoiesis and angiogenesis. Since HSP90 interacts with HIF1α, and HSP90 can be upregulated from heat acclimation in humans, we present a proposal that heat acclimation can mimic molecular adaptations to those of altitude exposure. Specifically, we propose that heat acclimation increases HSP90 which then stabilizes HIF1α in a normoxic environment. This has many implications since HIF1α regulates red blood cell and vasculature formation. In this paper we will discuss (1) the functional roles of HSP90 and HIF1α, (2) the interaction between HSP90 and other client proteins including HIF1α, and (3) results from in vitro studies that may suggest how the relationship between HSP90 and HIF1α might be applied to individuals preparing to make altitude sojourns.

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 EXTH-54. ENHANCED SENSITIVITY OF HUMAN GLIOMA CELLS FOR TEMOZOLOMIDE (TMZ) BY COMBINING THERAPY WITH HEAT SHOCK PROTEIN 90

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii99-ii99
Author(s):  
Pratibha Sharma ◽  
Lakshmi Shree K Mahadevan ◽  
Aaron Argall ◽  
Jihong Xu ◽  
Deepa Sampath ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Blood Brain Barrier ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Heat Shock Protein 90 ◽  
Brain Barrier ◽  
Client Proteins

Abstract BACKGROUND Heat-shock protein 90 (HSP90) is a molecular chaperone involved in the conformational maturation of many client proteins that regulate cell proliferation, survival, and apoptosis. Due to the limited solubility of natural Hsp90 inhibitors, synthetic inhibitors with a more potent impact are being developed. In this study we examined the biological activity of a potent synthetic small molecule Hsp90 inhibitor, SNX-5422 (PF-04929113)and assessed its ability of to inhibit the growth of glioma and to synergize with temozolomide. We also examined the ability of SNX-5422 to cross the blood brain barrier (BBB) and to achieve target inhibition in vivo. METHODS Using a combination of in vitro techniques, the effect of SNX-5422 on the biological impact and HSP90 client protein signaling were studied in glioma lines and patient-derived glioma stem like cells. Its efficacy as a single agent or in combination with TMZ was also assessed in vitro. To assess SNX-5422 ability to cross blood brain barrier, brain and plasma pharmacokinetics was performed in non-tumor bearing mice. RESULTS SNX-5422 exhibited potent growth inhibition in both glioma cells and GSCs with an IC50 range of 100-500nM, and inhibited pro-survival signal kinases, phospho-Akt, p-ERK1/2 and p-S6 following treatment in GSC262 and GSC811. This was accompanied by accumulation of apoptotic cells following SNX-5422 exposure. Combination studies with TMZ showed a synergestic impact on glioma cell proliferation. Pharmacokinetics studies showed a significant drug penetrance into the intact brain further supported by elevated levels of HSP70 (molecular maker for HSP90 inhibition) by IHC. CONCLUSIONS SNX-5422 is effective in downregulating Hsp90 client proteins required for glioma cell survival. In addition, SNX-5422 inhibits tumor growth by promoting apoptosis through modulation of several key signaling pathways and sensitizes glioma cells to TMZ. Given also that SNX-5422 crosses BBB, it warrants further investigation as a clinical agent for treatment of gliomas.

scholarly journals In vitro and in vivo role of heat shock protein 90 in Amphotericin B resistance of Aspergillus terreus

2013 ◽  
Vol 19 (1) ◽  
pp. 50-55 ◽  
Author(s):  
G. Blum ◽  
B. Kainzner ◽  
K. Grif ◽  
H. Dietrich ◽  
B. Zeiger ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Amphotericin B ◽  
Aspergillus Terreus ◽  
Heat Shock Protein 90

scholarly journals Detrimental Role of Heat Shock Protein 60&70 and Toll-like Receptor 4 in Skeletal Muscle Ischaemia In Vitro

2013 ◽  
Vol 57 (5) ◽  
pp. 77S
Author(s):  
Ali Navi ◽  
Rebekah Yu ◽  
Xu Shi-Wen ◽  
Sidney Shaw ◽  
George Hamilton ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 60 ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Muscle Ischaemia
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