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           Search results for: NVP-AUY-922 Mechanisms: Hsp90 inhibitor   

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#28977641   2017/10/04 Save this To Up

PP32 and SET/TAF-Iβ proteins regulate the acetylation of newly synthesized histone H4.

Newly synthesized histones H3 and H4 undergo a cascade of maturation steps to achieve proper folding and to establish post-translational modifications prior to chromatin deposition. Acetylation of H4 on lysines 5 and 12 by the HAT1 acetyltransferase is observed late in the histone maturation cascade. A key question is to understand how to establish and regulate the distinct timing of sequential modifications and their biological significance. Here, we perform proteomic analysis of the newly synthesized histone H4 complex at the earliest time point in the cascade. In addition to known binding partners Hsp90 and Hsp70, we also identify for the first time two subunits of the histone acetyltransferase inhibitor complex (INHAT): PP32 and SET/TAF-Iβ. We show that both proteins function to prevent HAT1-mediated H4 acetylation in vitro. When PP32 and SET/TAF-Iβ protein levels are down-regulated in vivo, we detect hyperacetylation on lysines 5 and 12 and other H4 lysine residues. Notably, aberrantly acetylated H4 is less stable and this reduces the interaction with Hsp90. As a consequence, PP32 and SET/TAF-Iβ depleted cells show an S-phase arrest. Our data demonstrate a novel function of PP32 and SET/TAF-Iβ and provide new insight into the mechanisms regulating acetylation of newly synthesized histone H4.

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#28915605   2017/09/16 Save this To Up

HSP90 inhibitor 17-DMAG exerts anticancer effects against gastric cancer cells principally by altering oxidant-antioxidant balance.

Heat shock protein 90 (HSP90) stabilizes numerous oncoproteins and, therefore, its inhibition has emerged as a promising antineoplastic strategy for diverse malignancies. In this study, we determined the therapeutic effects and mechanisms of action of a specific HSP90 inhibitor, 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG), in gastric cancer cell lines (AGS, SNU-1, and KATO-III), patient-derived tissues, and a mouse xenograft model. 17-DMAG exerted anticancer effects against gastric cancer cells, manifested by significantly decreased proliferation rates (P < 0.05) and increased expression of apoptotic markers. Flow cytometry using dichlorofluorescein (DCF) diacetate revealed that 17-DMAG dose-dependently increases reactive oxygen species (ROS) levels in gastric cancer cells. Inhibition of ROS by N-acetyl-L-cysteine (NAC) abrogated the proapoptotic effects of 17-DMAG, as demonstrated by the decreased expression of proapoptotic proteins. In addition, 17-DMAG dose- and time-dependently reduced the expression of antioxidants such as catalase and glutathione peroxidase (GPx). Moreover, 17-DMAG reduced the expression of nuclear respiratory factor (NRF)-1 and NRF-2, and prevented them from migrating from the cytoplasm to the nucleus dose-dependently. Finally, in a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with 17-DMAG than in control mice (P < 0.05). Taken altogether, our results suggest that 17-DMAG exerts potent antineoplastic activity against gastric cancer cells primarily by promoting ROS generation and suppressing antioxidant enzyme activities.

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17 DMAG 17 DMAG Proteinase Inhibitor 9 (P Nrf antioxidant pathway A NVP-AUY-922 Mechanisms: H NVP-HSP-990 Mechanisms: H BYL-719 Mechanisms: PI3K- AT-13387 Mechanisms: Hsp9 Dog Receptor-binding canc GI cancer (gastric, colon GI cancer (esophageal, ga Cancer Samples: Gastric

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#28842319   2017/08/26 Save this To Up

Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib.

Acquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapies to overcome resistance represents an unmet need. Understanding the signalling that drives drug resistance will facilitate the development of new salvage therapies to treat patients with secondary TKI resistance. In this study, we utilise mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7% of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance, respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatory pathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signalling pathway. Drug response profiling rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.

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#28841232   2017/08/25 Save this To Up

Inhibiting heat shock protein 90 and the ubiquitin-proteasome pathway impairs metabolic homeostasis and leads to cell death in human pancreatic cancer cells.

Heat shock protein 90 (HSP90) and the ubiquitin-proteasome pathway play crucial roles in the homeostasis of pancreatic cancer cells. This study combined for the first time the HSP90 inhibitor ganetespib (Gan) and the proteasome inhibitor carfilzomib (Carf) to target key mechanisms of homeostasis in pancreatic cancer. It was hypothesized that Gan plus Carf would elicit potent antitumor activity by modulating complementary homeostatic processes.

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#28822683   2017/08/20 Save this To Up

Hsp90 Sensitivity to ADP Reveals Hidden Regulation Mechanisms.

The ATPase cycle of the Hsp90 molecular chaperone is essential for maintaining the stability of numerous client proteins. Extensive analysis has focused on ATP-driven conformational changes of Hsp90; however, little is known about how Hsp90 operates under physiological nucleotide conditions in which both ATP and ADP are present. By quantifying Hsp90 activity under mixed nucleotide conditions, we find dramatic differences in ADP sensitivity among Hsp90 homologs. ADP acts as a strong ATPase inhibitor of cytosol-specific Hsp90 homologs, whereas organellular Hsp90 homologs (Grp94 and TRAP1) are relatively insensitive to the presence of ADP. These results imply that an ATP/ADP heterodimer of cytosolic Hsp90 is the predominant active state under physiological nucleotide conditions. ADP inhibition of human and yeast cytosolic Hsp90 can be relieved by the cochaperone aha1. ADP inhibition of bacterial Hsp90 can be relieved by bacterial Hsp70 and an activating client protein. These results suggest that altering ADP inhibition may be a mechanism of Hsp90 regulation. To determine the molecular origin of ADP inhibition, we identify residues that preferentially stabilize either ATP or ADP. Mutations at these sites can both increase and decrease ADP inhibition. An accounting of ADP is critically important for designing and interpreting experiments with Hsp90. For example, contaminating ADP is a confounding factor in fluorescence resonance energy transfer experiments measuring arm closure rates of Hsp90. Our observations suggest that ADP at physiological levels is important to Hsp90 structure, activity, and regulation.

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#28789442   2017/08/09 Save this To Up

Effects of 17-allylamino-17-demethoxygeldanamycin on the induction of apoptosis and cell cycle arrest in HCT-116 cells.

The present study investigated the effects of HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on apoptosis and the cell cycle of the HCT-116 human colon carcinoma cell line, with the aim of elucidating their underlying mechanisms. MTT was used to examine the inhibitory effects of 17-AAG on the proliferation of HCT-116 cells at various time points and doses. The cells were stained with Annexin V-fluorescein isothiocyanate/propidium iodide and evaluated by flow cytometry. The expression of signal transducer and activator of transcription (STAT)3, cyclin D1, cytochrome c (cyt-c), caspase 9 and caspase 3 at the mRNA and protein level was determined using reverse transcription-polymerase chain reaction and western blotting. Treatment with 17-AAG at a concentration of 1.25-20 mg/l for 24 and 48 h significantly inhibited the proliferation of HCT-116 cells in a time-dependent and concentration-dependent manner. Treatment with 17-AAG at concentrations of 1.25, 2.5 and 5 mg/l for 48 h significantly induced apoptosis and cell cycle arrest in HCT-116 cells. Exposure to 17-AAG at concentrations of 1.25, 2.5 and 5 mg/l for 48 h significantly downregulated the mRNA and protein expression of STAT3 and cyclin D1, but upregulated cyt-c, caspase 9 and caspase 3 in a concentration-dependent manner in HCT-116 cells. Therefore 17-AAG is able to inhibit cell proliferation, inducing apoptosis and G1 stage cell cycle arrest by downregulating the expression of cyclin D1, and promoting the mitochondria apoptosis by downregulating STAT3 in HCT-116 cells.

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#28725954   2017/07/20 Save this To Up

Proteasome Stress Triggers Death of SH-SY5Y and T98G Cells via Different Cellular Mechanisms.

Overload or dysfunction of ubiquitin-proteasome system (UPS) is implicated in mechanisms of neurodegeneration associated with neurodegenerative diseases, e.g. Parkinson and Alzheimer disease, and ischemia-reperfusion injury. The aim of this study was to investigate the possible association between viability of neuroblastoma SH-SY5Y and glioblastoma T98G cells treated with bortezomib, inhibitor of 26S proteasome, and accumulation of ubiquitin-conjugated proteins with respect to direct cytotoxicity of aggregates of ubiquitin-conjugated proteins. Bortezomib-induced death of SH-SY5Y cells was documented after 24 h of treatment while death of T98G cells was delayed up to 48 h. Already after 4 h of treatment of both SH-SY5Y and T98G cells with bortezomib, increased levels of both ubiquitin-conjugated proteins with molecular mass more than 150 kDa and Hsp70 were observed whereas Hsp90 was elevated in T98G cells and decreased in SH-SY5Y cells. With respect to the cell death mechanism, we have documented bortezomib-induced activation of caspase 3 in SH-SY5Y cells that was probably a result of increased expression of pro-apoptotic proteins, PUMA and Noxa. In T98G cells, bortezomib-induced expression of caspase 4, documented after 24 h of treatment, with further activation of caspase 3, observed after 48 h of treatment. The delay in activation of caspase 3 correlated well with the delay of death of T98G cells. Our results do not support the possibility about direct cytotoxicity of aggregates of ubiquitin-conjugated proteins. They are more consistent with a view that proteasome inhibition is associated with both transcription-dependent and -independent changes in expression of pro-apoptotic proteins and consequent cell death initiation associated with caspase 3 activation.

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#28642708   2017/06/23 Save this To Up

Myricitrin Protects Cardiomyocytes from Hypoxia/Reoxygenation Injury: Involvement of Heat Shock Protein 90.

Modulation of oxidative stress is therapeutically effective in ischemia/reperfusion (I/R) injury. Myricitrin, a naturally occurring phenolic compound, is a potent antioxidant. However, little is known about its effect on I/R injury to cardiac myocytes. The present study was performed to investigate the potential protective effect of myricitrin against hypoxia/reoxygenation (H/R)-induced H9c2 cardiomyocyte injury and its underlying mechanisms. Myricitrin pretreatment improved cardiomyocyte viability, inhibited ROS generation, maintained the mitochondrial membrane potential, reduced apoptotic cardiomyocytes, decreased the caspase-3 activity, upregulated antiapoptotic proteins and downregulated proapoptotic proteins during H/R injury. Moreover, the potential targets of myricitrin was predicted using Discovery Studio software, and heat shock protein 90 (Hsp90) was identified as the main disease-related target. Further mechanistic investigation revealed that 17-AAG, a pharmacologic inhibitor of Hsp90, significantly blocked the myricitrin-induced cardioprotective effect demonstrated by increased apoptosis and ROS generation. These results suggested that myricitrin provides protection to H9c2 cardiomyocytes against H/R-induced oxidative stress and apoptosis, most likely via increased expression of Hsp90.

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#28624441   2017/06/18 Save this To Up

Hsp90 inhibitor geldanamycin attenuates the cytotoxicity of sunitinib in cardiomyocytes via inhibition of the autophagy pathway.

Sunitinib malate (sunitinib) is an orally available, multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Although sunitinib is effective for the treatment of patients with gastrointestinal stromal tumor, advanced renal cell carcinoma, or pancreatic neuroendocrine tumor, adverse cardiac events associated with sunitinib administration have been reported. Here, we examined the effect of geldanamycin, an inhibitor of heat shock protein (Hsp) 90, on sunitinib-induced cytotoxicity in cardiomyocytes. First, we found that treatment with geldanamycin or other Hsp90 inhibitors (tanespimycin, ganetespib, or BIIB021) significantly attenuated sunitinib-induced cytotoxicity in rat H9c2 cardiomyocytes, suggesting a drug-class effect of Hsp90 inhibitors. We then examined the mechanisms underlying sunitinib-induced cytotoxicity and found that sunitinib induced autophagy in H9c2 cells and that pretreatment with geldanamycin inhibited the induction of autophagy by promoting degradation of the autophagy-related proteins Atg7, Beclin-1, and ULK1. Pharmacological assessment with autophagy inhibitors confirmed that geldanamycin attenuated the cytotoxicity of sunitinib by interfering with autophagy. In addition, we found that the molecular chaperone Hsp70, which is induced by geldanamycin, was not involved in the attenuation of sunitinib-induced cytotoxicity. Finally, to provide more clinically relevant data, we confirmed that geldanamycin attenuated sunitinib-induced cytotoxicity in human induced pluripotent stem cell-derived cardiomyocytes. Together, these data suggest that geldanamycin attenuates sunitinib-induced cytotoxicity in cardiomyocytes by inhibiting the autophagy pathway. Thus, the further investigation of combination or sequential treatment with an Hsp90 inhibitor and sunitinib is warranted as a potential strategy of attenuating the cardiotoxicity associated with sunitinib administration in the clinical setting.

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#28551637   2017/05/28 Save this To Up

17-Allylamino-17-demethoxygeldanamycin-induced Changes in [(18)F]Fluorothymidine Uptake.

The proliferation status of tumor cells can be imaged using [(18)F]fluorothymidine ([(18)F]FLT), which is trapped by cell cycle-dependent thymidine kinase 1 (TK1). Targeting of heat shock protein 90 (HSP90) disrupts multiple client proteins, leading to heterogeneous cell-cycle phenotypes. To investigate whether [(18)F]FLT uptake reflects the growth arrest caused by various mechanisms of HSP90 inhibition, we used HCT116 cells that were arrested at G0/G1 phase, and Hep3B cells at G2/M phase, by the HSP90 inhibitor 17-AAG. In HCT116 cells, 17-AAG did not induce significant changes in [(18)F]FLT uptake despite the decreased expression of TK1, cyclin A, and cyclin B. The mRNA level of 5'3'-deoxynucleotidase 1 (NT5C), which antagonizes TK1 by de-phosphorylating [(18)F]FLT monophosphate, was also decreased in 17-AAG-treated HCT116 cells by 55.3±18.1% compared to vehicle-treated cells. In Hep3B cells, 17-AAG treatment did not induce TK1 expression, TK1 activity nor [(18)F]FLT uptake. Nucleoside transporter activity in the plasma membrane was unchanged in both cell lines. These results showed that a HSP90 inhibitor exerts multifaceted effects on [(18)F]FLT uptake before inducing cell death in a cell-cycle-independent manner. Therefore, the use of [(18)F]FLT-positron emission tomography for monitoring treatment by HSP90 inhibitor would be more appropriate when tumor cell death is induced after growth arrest.

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