TY - JOUR
T1 - Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells
AU - Eskew, Jeffery D.
AU - Sadikot, Takrima
AU - Morales, Pedro
AU - Duren, Alicia
AU - Dunwiddie, Irene
AU - Swink, Megan
AU - Zhang, Xiaoying
AU - Hembruff, Stacey
AU - Donnelly, Alison
AU - Rajewski, Roger A.
AU - Blagg, Brian S.J.
AU - Manjarrez, Jacob R.
AU - Matts, Robert L.
AU - Holzbeierlein, Jeffrey M.
AU - Vielhauer, George A.
N1 - Funding Information:
*These studies were supported in part by the following grants: NIH Grants R01 CA125392, CA120458, the Oklahoma Agricultural Experiment Station [Project No. 1975] and.in part by the Kansas Technology Enterprise Corporation through the Centers of Excellence Program. Finally, the authors would like to thank the other members of the Hsp90 Research Consortium, whose efforts and expertise made this research possible: John D. Robertson, Katherine F. Roby, Len M. Neckers, Joanna Krise, and MehmetTanol.
PY - 2011/10/31
Y1 - 2011/10/31
N2 - Background: The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described, which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel approach to characterize Hsp90 inhibition in cancer cells.Methods: PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays (DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity and size exclusion chromatography) to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies.Results: KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model.Conclusions: Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer.
AB - Background: The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described, which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel approach to characterize Hsp90 inhibition in cancer cells.Methods: PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays (DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity and size exclusion chromatography) to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies.Results: KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model.Conclusions: Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer.
KW - C-terminal inhibitors
KW - Hsp90
KW - N-terminal inhibitors
KW - Novobiocin
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=80054995372&partnerID=8YFLogxK
U2 - 10.1186/1471-2407-11-468
DO - 10.1186/1471-2407-11-468
M3 - Article
C2 - 22039910
AN - SCOPUS:80054995372
SN - 1471-2407
VL - 11
JO - BMC Cancer
JF - BMC Cancer
M1 - 468
ER -