n2-(1h-indazole-5-yl)-n6-methyl-3-nitropyridine-2-6-diamine has been researched along with Neoplasms* in 2 studies
1 review(s) available for n2-(1h-indazole-5-yl)-n6-methyl-3-nitropyridine-2-6-diamine and Neoplasms
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Regulating the master regulator: Controlling heat shock factor 1 as a chemotherapy approach.
Described is the role that heat shock factor 1 (HSF1) plays in regulating cellular stress. Focusing on the current state of the HSF1 field in chemotherapeutics we outline the cytoprotective role of HSF1 in the cell. Summarizing the mechanism by which HSF1 regulates the unfolded proteins that are generated under stress conditions provides the background on why HSF1, the master regulator, is such an important protein in cancer cell growth. Summarizing siRNA knockdown results and current inhibitors provides a comprehensive evaluation on HSF1 and its current state. One set of molecules stands out, in that they completely obliterate the levels of HSF1, while simultaneously inhibiting heat shock protein 90 (Hsp90). These molecules are extremely promising as chemotherapeutic agents and as tools that may ultimately provide the connection between Hsp90 inhibition and HSF1 protein levels. Topics: HSP90 Heat-Shock Proteins; Humans; Neoplasms; Transcription Factors | 2015 |
1 other study(ies) available for n2-(1h-indazole-5-yl)-n6-methyl-3-nitropyridine-2-6-diamine and Neoplasms
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KRIBB11 inhibits HSP70 synthesis through inhibition of heat shock factor 1 function by impairing the recruitment of positive transcription elongation factor b to the hsp70 promoter.
Heat shock factor 1 (HSF1) is the master switch for heat shock protein (HSP) expression in eukaryotes. A synthetic chemical library was screened to identify inhibitors of HSF1 using a luciferase reporter under the control of a heat shock element. A compound named KRIBB11 (N(2)-(1H-indazole-5-yl)-N(6)-methyl-3-nitropyridine-2,6-diamine) was identified for its activity in abolishing the heat shock-induced luciferase activity with an IC(50) of 1.2 μmol/liter. When the cells were exposed to heat shock in the presence of KRIBB11, the induction of HSF1 downstream target proteins such as HSP27 and HSP70 was blocked. In addition, treatment of HCT-116 cells with KRIBB11 induced growth arrest and apoptosis. Markers of apoptosis, such as cleaved poly(ADP-ribose) polymerase, were detected after KRIBB11 treatment. Biotinyl-KRIBB11 was synthesized as an affinity probe for the identification of KRIBB11 target proteins. Using affinity chromatography and competition assays, KRIBB11 was shown to associate with HSF1 in vitro. Chromatin immunoprecipitation analysis showed that KRIBB11 inhibited HSF1-dependent recruitment of p-TEFb (positive transcription elongation factor b) to the hsp70 promoter. Finally, intraperitoneal treatment of nude mice with KRIBB11 at 50 mg/kg resulted in a 47.4% (p < 0.05) inhibition of tumor growth without body weight loss. Immunoblotting assays showed that the expression of HSP70 was lower in KRIBB11-treated tumor tissue than in control tissues. Because HSPs are expressed at high levels in a wide range of tumors, these results strengthen the rationale for targeting HSF1 in cancer therapy. Topics: Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Diamines; DNA-Binding Proteins; Drug Delivery Systems; Heat Shock Transcription Factors; Heat-Shock Proteins; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Indazoles; Mice; Mice, Nude; Molecular Chaperones; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms; Poly(ADP-ribose) Polymerases; Positive Transcriptional Elongation Factor B; Promoter Regions, Genetic; Transcription Factors | 2011 |