Show simple item record

dc.contributor.authorComer, Shawna B.
dc.contributor.authorVielhauer, George A.
dc.contributor.authorManthe, Craig A.
dc.contributor.authorChaguturu, Vamsee K.
dc.contributor.authorSzabla, Kristen
dc.contributor.authorMatts, Robert L.
dc.contributor.authorDonnelly, Alison C.
dc.contributor.authorBlagg, Brian S. J.
dc.contributor.authorHolzbeierlein, Jeffery M.
dc.identifier.citationShawna, 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.
dc.description.abstractPURPOSE: 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.en_US
dc.rightsThis is the peer reviewed version of the following article: Prostate, which has been published in final form at This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
dc.subjectHsp90 inhibitorsen_US
dc.subjectProstate canceren_US
dc.titleCharacterization of a novel novobiocin analogue as a putative Cterminal inhibitor of heat shock protein 90 in prostate cancer cellsen_US
kusw.kuauthorDonnelly, Alison C.
kusw.kuauthorBlagg, Brian S. J.
kusw.kudepartmentMedicinal Chemistryen_US
kusw.oanotesPer SHERPA 3/28/2017: Author's Pre-print: green tick author can archive pre-print (ie pre-refereeing) Author's Post-print: grey tick subject to Restrictions below, author can archive post-print (ie final draft post-refereeing) Restrictions:

12 months embargo

Publisher's Version/PDF: cross author cannot archive publisher's version/PDF General Conditions:

Some journals have separate policies, please check with each journal directly On author's personal website, institutional repositories, arXiv, AgEcon, PhilPapers, PubMed Central, RePEc or Social Science Research Network Author's pre-print may not be updated with Publisher's Version/PDF Author's pre-print must acknowledge acceptance for publication Non-Commercial Publisher's version/PDF cannot be used Publisher source must be acknowledged with citation Must link to publisher version with set statement (see policy) If OnlineOpen is available, BBSRC, EPSRC, MRC, NERC and STFC authors, may self-archive after 12 months
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

Files in this item


This item appears in the following Collection(s)

Show simple item record