scholarly journals Targeting heat shock protein 72 enhances Hsp90 inhibitor-induced apoptosis in myeloma

Leukemia ◽  
2010 ◽  
Vol 24 (10) ◽  
pp. 1804-1807 ◽  
Author(s):  
E L Davenport ◽  
A Zeisig ◽  
L I Aronson ◽  
H E Moore ◽  
S Hockley ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Hsp90 Inhibitor ◽  
Heat Shock Protein 72 ◽  
Induced Apoptosis

Extracellular heat shock protein 72 protects schwann cells from hydrogen peroxide-induced apoptosis

2012 ◽  
Vol 90 (6) ◽  
pp. 1261-1269 ◽  
Author(s):  
Xinjing Luo ◽  
Lingjian Tao ◽  
Peng Lin ◽  
Xuanrong Mo ◽  
Haixiao Chen
Keyword(s):  
Hydrogen Peroxide ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Schwann Cells ◽  
Heat Shock Protein 72 ◽  
Induced Apoptosis

scholarly journals Superior Activity of BET Protein Bromodomain Antagonist-Based Combination with JAK Kinase, PIM Kinase or Heat Shock Protein 90 Inhibitor Against Post-MPN-MF sAML Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1269-1269 ◽  
Author(s):  
Dyana T Saenz ◽  
Warren Fiskus ◽  
Taghi Manshouri ◽  
Baohua Sun ◽  
Stephanie Krieger ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Hsp90 Inhibitor ◽  
Genetic Alterations ◽  
Continuous Exposure ◽  
Jak Inhibitor ◽  
Jak Kinase ◽  
Induced Apoptosis

Abstract Myeloproliferative Neoplasms with myelofibrosis (MPN-MF) demonstrate constitutive activation of the JAK-STAT signaling and often progress (~20%) to AML (sAML). As a single agent, JAK1&2 inhibitor ruxolitinib confers significant clinical benefit in MPN-MF, but exhibits modest activity in sAML, which is also incurable with standard anthracycline and Ara-C-based chemotherapy. This supports the rationale to develop and test novel combination therapies for post-MPN-MF sAML. Genetic alterations documented in sAML include those in JAK2, MPL or calreticulin (CALR) gene, as well as in TP53, TET2, ASXL1, IDH1&2, SRSF2, RUNX1, MYC, PTPN11, NRAS, and SETBP1 genes. Variant allelic frequency analyses demonstrated a common co-occurrence of JAK2V617F and mutant TP53 in the dominant clones of sAML. We and others have previously reported that treatment with BET (bromodomain and extra-terminal) protein bromodomain antagonists (BA) results in growth arrest, differentiation and apoptosis of AML cells (Mol Cancer Ther 2014,13:2315). In the present studies, we demonstrate that treatment with JQ1 but not its inactive enantiomer (R-JQ1) dose-dependently (100 to 2000 nM) mediates growth inhibition and apoptosis of the cultured (HEL92.1.7, SET2 and UKE1 cells) and primary (p) post-MPN-MF sAML cells. JQ1 treatment reduced the promoter occupancy of BRD4 and RNA polymerase II on MYC, BCL2 and IL7R promoters, attenuated the mRNA and protein expressions of BCL2, BCL-xL, MYC, CDK4/6 and PIM1, and repressed the pSTAT5 and pSTAT3 levels, while concomitantly inducing the levels of HEXIM1, p21, p27 and BIM in the sAML cells. Following engraftment of NOD/scid/IL-2Rγ null) (NSG) mice with HEL92.1.7 cell xenografts, treatment with JQ1 (50 mg/kg/day, administered IP daily x 5 days per week x 3 weeks) also significantly improved the median survival of the mice (p < 0.01). Compared to treatment with each agent alone, co-treatment with JQ1 and ruxolitinib (100 to 1000 nM) or pacritinib (250 to 1000 nM), which is also a clinically active JAK2, JAK2-V617F and Fms-like tyrosine kinase 3 inhibitor that does not inhibit JAK1, was synergistically lethal against the cultured sAML cells (Combination indices of < 1.0 on the isobologram analyses). Additionally, co-treatment with JQ1 and ruxolitinib caused a marked inhibition of pJAK2, pSTAT5, pSTAT3, MYC, CDK4/6, BCL-xL and PIM1 in the sAML cells. Co-treatment with JQ1 and the pan-PIM kinase inhibitor AZD1208 (500-3000 nM), which inhibits the PIM kinase substrates BAD, p70S6 kinase and 4EBP1, also synergistically induced apoptosis of the cultured sAML cells (CI < 1.0). HEL92.1.7 and SET2 cells are not only positive for the JAK2V617F mutation, they also express mutant TP53 (M133K in HEL92.1.7 and R248W in SET2 cells). Co-treatment with JQ1 and the heat shock protein (HSP) 90 inhibitor AUY922 (2.5-20 nM), which is known to down-regulate the levels of mutant-TP53, JAK2, c-RAF, pSTAT5, pSTAT3 and pAKT, is synergistically lethal against HEL92.1.7 and SET2 cells. We have isolated JAK inhibitor-resistant HEL92.1.7 cells (> 10-fold resistant to ruxolitinib; HEL/JIR cells) under the in vitro selection pressure of a continuous exposure to JAK inhibitor (Clin Cancer Res 2011;17:7347). Compared to the parental HEL92.1.7, HEL/JIR cells are highly and collaterally sensitive to AUY922. HEL/JIR cells also remain sensitive to JQ1-induced apoptosis. Importantly, co-treatment with JQ1 and AUY922 is also synergistically lethal against HEL/JIR cells (CI < 1.0). Taken together, these findings highlight the pre-clinical activity of BA-based combination with JAK inhibitors (ruxolitinib or pacritinib), PIM kinase inhibitor (AZD1208) or HSP90 inhibitor (AUY922) against JAK kinase inhibitor-sensitive sAML, as well as of the BA-based combination with HSP90 inhibitor or pan-PIM kinase inhibitor against JAK inhibitor-resistant sAML cells. Collectively, these findings also support further in vivo testing of these BA-based combinations against sAML cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Heat Shock Protein 72 Modulates Pathways of Stress-induced Apoptosis

1998 ◽  
Vol 273 (27) ◽  
pp. 17147-17153 ◽  
Author(s):  
Katherine A. Buzzard ◽  
Amato J. Giaccia ◽  
Marilyn Killender ◽  
Robin L. Anderson
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 72 ◽  
Induced Apoptosis

Selectively Sensitizing Malignant Cells to Photothermal Therapy Using a CD44-Targeting Heat Shock Protein 72 Depletion Nanosystem

ACS Nano ◽  
2016 ◽  
Vol 10 (9) ◽  
pp. 8578-8590 ◽  
Author(s):  
Shouju Wang ◽  
Ying Tian ◽  
Wei Tian ◽  
Jing Sun ◽  
Shuang Zhao ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Photothermal Therapy ◽  
Malignant Cells ◽  
Heat Shock Protein 72 ◽  
Cd44 Targeting

scholarly journals Synergism of Heat Shock Protein 90 and Histone Deacetylase Inhibitors in Synovial Sarcoma

Sarcoma ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Anne Nguyen ◽  
Le Su ◽  
Belinda Campbell ◽  
Neal M. Poulin ◽  
Torsten O. Nielsen
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Synovial Sarcoma ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Therapeutic Benefit ◽  
Multiple Time

Current systemic therapies have little curative benefit for synovial sarcoma. Histone deacetylase (HDAC) inhibitors and the heat shock protein 90 (Hsp90) inhibitor 17-AAG have recently been shown to inhibit synovial sarcoma in preclinical models. We tested combinations of 17-AAG with the HDAC inhibitor MS-275 for synergism by proliferation and apoptosis assays. The combination was found to be synergistic at multiple time points in two synovial sarcoma cell lines. Previous studies have shown that HDAC inhibitors not only induce cell death but also activate the survival pathway NF-κB, potentially limiting therapeutic benefit. As 17-AAG inhibits activators of NF-κB, we tested if 17-AAG synergizes with MS-275 through abrogating NF-κB activation. In our assays, adding 17-AAG blocks NF-κB activation by MS-275 and siRNA directed against histone deacetylase 3 (HDAC3) recapitulates the effects of MS-275. Additionally, we find that the NF-κB inhibitor BAY 11-7085 synergizes with MS-275. We conclude that agents inhibiting NF-κB synergize with HDAC inhibitors against synovial sarcoma.

scholarly journals Hypertension, aging, and myocardial synthesis of heat-shock protein 72.

Hypertension ◽  
1994 ◽  
Vol 24 (5) ◽  
pp. 620-624 ◽  
Author(s):  
M Bongrazio ◽  
L Comini ◽  
G Gaia ◽  
T Bachetti ◽  
R Ferrari
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 72

scholarly journals L-NAME Treatment Enhances Exercise-induced Content of Myocardial Heat Shock Protein 72 (Hsp72) in Rats

2011 ◽  
Vol 27 (5) ◽  
pp. 479-486 ◽  
Author(s):  
Wellington Lunz ◽  
Luciano S.A. Capettini ◽  
Ana P.C. Davel ◽  
Carolina D. Munhoz ◽  
Josiane F. da Silva ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 72 ◽  
Exercise Induced
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