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    Characterization of a novel novobiocin analogue as a putative Cterminal inhibitor of heat shock protein 90 in prostate cancer cells

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    Donnelly_2010.pdf (723.6Kb)
    Issue Date
    2010-01-01
    Author
    Comer, Shawna B.
    Vielhauer, George A.
    Manthe, Craig A.
    Chaguturu, Vamsee K.
    Szabla, Kristen
    Matts, Roberts L.
    Donnelly, Alison C.
    Blagg, Brian S. J.
    Holzbeierlein, Jeffrey
    Publisher
    Wiley
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    This is the peer reviewed version of the following article: Prostate, which has been published in final form at http://dx.doi.org/10.1002/pros.21035. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
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    Abstract
    PURPOSE: Hsp90 is important in the folding, maturation and stabilization of pro-tumorigenic client proteins and represents a viable drug target for the design of chemotherapies. Previously, we reported the development of novobiocin analogues designed to inhibit the C-terminal portion of Hsp90, which demonstrated the ability to decrease client protein expression. We now report the characterization of the novel novobiocin analogue, F-4, which demonstrates improved cytotoxicity in prostate cancer cell lines compared to the N-terminal inhibitor, 17-AAG. MATERIALS AND METHODS: LNCaP and PC-3 cells were treated with 17-AAG or F-4 in anti-proliferative, apoptosis, cell cycle and cytotoxicity assays. Western blot and prostate specific antigen (PSA) ELISAs were used to determine client protein degradation, induction of Hsp90 and to assess the functional status of the androgen receptor (AR) in response to F-4 treatment. Surface Plasmon Resonance (SPR) was also used to determine the binding properties of F-4 to Hsp90. RESULTS: F-4 demonstrated improved potency and efficacy compared to novobiocin in anti-proliferative assays and decreased expression of client proteins. PSA secretion was inhibited in a dose-dependent manner that paralleled a decrease in AR expression. The binding of F-4 to Hsp90 was determined to be saturable with a binding affinity (Kd) of 100 µM. In addition, superior efficacy was demonstrated by F-4 compared to 17-AAG in experiments measuring cytotoxicity and apoptosis. CONCLUSIONS: These data reveal distinct modes of action for N-terminal and C-terminal Hsp90 inhibitors, which may offer unique therapeutic benefits for the treatment of prostate cancer.
    URI
    http://hdl.handle.net/1808/23502
    DOI
    https://doi.org/10.1002/pros.21035
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    • Medicinal Chemistry Scholarly Works [196]
    Citation
    Shawna, B. C., George, A. V., Craig, A. M., Vamsee, K. C., Kristen, S., Robert, L. M., … Jeffrey, M. H. (2010). Characterization of a novel novobiocin analogue as a putative C-terminal inhibitor of heat shock protein 90 in prostate cancer cells. The Prostate, 70(1), 27–36. http://doi.org/10.1002/pros.21035

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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