Disease relevance of Hsp84-2

• When administered in vivo to mice bearing MDA-MB-468 human breast cancer xenografted tumors, these agents result in pharmacologically relevant concentrations and, accordingly, in modulation of Hsp90-client proteins in tumors [1].
• Characterization of heat-inducible expression and cloning of HtpG (Hsp90 homologue) of Porphyromonas gingivalis [2].

High impact information on Hsp84-2

• Modulating molecular chaperone Hsp90 functions through reversible acetylation [3].
• Molecular chaperone heat shock protein 90beta (Hsp90beta)-bound Ack1 and treatment of cells with geldanamycin, a Hsp90 inhibitor, inhibited Ack1 kinase activity and suppressed tumorigenesis [4].
• Its Hsp90 inhibition results in multiple anti-tumor-specific effects, such as degradation of Hsp90-client proteins involved in cell growth, survival, and specific transformation, inhibition of cancer cell growth, delay of cell cycle progression, induction of morphological and functional changes, and apoptosis [5].
• A role for the Hsp90 molecular chaperone family in antigen presentation to T lymphocytes via major histocompatibility complex class II molecules [6].
• The PU-class, a purine-scaffold Hsp90 inhibitor series, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer [1].

Biological context of Hsp84-2

• These results show that Hsp90 can function at different levels within apoptotic signal transduction pathways [7].
• Pharmacological inhibition of Hsp90 activity in IFN-gamma-treated APC resulted in severe abrogation of MHCII-restricted presentation of cytosolic antigen, but only partially inhibited exogenous antigen presentation [6].
• The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented [1].
• For example, Hsp90 homologues in several microbial species have been shown to contribute to virulence [2].
• Further, pharmacological Hsp90 inhibition reduced, while retroviral Hsp90 overexpression enhanced, the levels of stable compact MHCII heterodimers correlating with the antigen presentation phenotype [6].

Anatomical context of Hsp84-2

• Treatment of mouse antigen-presenting cells (APC) with the pharmacological Hsp90 inhibitor, geldanamycin, inhibited MHCII-mediated presentation of endocytosed and cytosolic proteins as well as synthetic peptides to specific T cells [6].
• Finally, we showed for the first time that Hsp90 inhibitors also reduce expression of VEGFR-1 on human vascular endothelial cells, VEGFR-3 on lymphatic endothelial cells in vitro, and all three VEGFRs on mouse vasculature in vivo [8].
• CONCLUSIONS: Inhibition of Hsp90 by 17AAG resulted in altered phospholipid metabolism in cultured tumor cells and in tumor xenografts [9].

Associations of Hsp84-2 with chemical compounds

• Furthermore, disrupting the function of Hsp90 by the addition of its specific inhibitor, geldanamycin, blocked Hsp90's protection of Bid cleavage [7].
• One of such inhibitors, the purine-scaffold class, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer [10].
• It represents a class of drugs, the benzoquinone ansamycin antibiotics, capable of binding and disrupting the function of Hsp90, leading to the depletion of multiple oncogenic client proteins [11].
• In the absence of Hsp90 inhibitors, NAC stimulated the activation of MAP kinase in BCR-ABL-transformed but not in the parental Rat1 cells [12].
• The increases observed in phosphocholine and phosphomonoester levels suggest that these metabolites may have the potential to act as noninvasive pharmacodynamic markers for analyzing tumor response to treatment with 17AAG or other Hsp90 inhibitors [9].

Analytical, diagnostic and therapeutic context of Hsp84-2

• RESULTS: Preclinical studies have demonstrated that disruption of many client proteins chaperoned by Hsp90 is achievable and associated with significant growth inhibition, both in vitro and in tumor xenografts [11].
• Hsp90 client protein expression was determined by using western blots [9].
• Hsp90 mRNA was cloned from a clinical isolate of C. albicans, converted to cDNA and cloned into vaccination plasmid pVAX1 [13].

References