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Eur Urol. 2014 Jul;66(1):145-55. doi: 10.1016/j.eururo.2013.12.019. Epub 2013 Dec 29.

Suppression of heat shock protein 27 using OGX-427 induces endoplasmic reticulum stress and potentiates heat shock protein 90 inhibitors to delay castrate-resistant prostate cancer.

Author information

1
The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
2
Oncology Research, Pfizer Worldwide Research & Development, San Diego, CA, USA.
3
The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Electronic address: m.gleave@ubc.ca.

Abstract

BACKGROUND:

Although prostate cancer responds initially to androgen ablation therapies, progression to castration-resistant prostate cancer (CRPC) frequently occurs. Heat shock protein (Hsp) 90 inhibition is a rational therapeutic strategy for CRPC that targets key proteins such as androgen receptor (AR) and protein kinase B (Akt); however, most Hsp90 inhibitors trigger elevation of stress proteins like Hsp27 that confer tumor cell survival and treatment resistance.

OBJECTIVE:

We hypothesized that cotargeting the cytoprotective chaperone Hsp27 and Hsp90 would amplify endoplasmic reticulum (ER) stress and treatment-induced cell death in cancer.

DESIGN, SETTING, AND PARTICIPANTS:

Inducible and constitutive Hsp27 and other HSPs were measured by real-time reverse transcription-polymerase chain reaction and immunoblot assays. The combinations of OGX-427 with Hsp90 inhibitors were evaluated in vitro for LNCaP cell growth and apoptosis and in vivo in CRPC LNCaP xenograft models.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

Tumor volumes were compared using the Kruskal-Wallis test. Overall survival was analyzed using Kaplan-Meier curves, and statistical significance was assessed with the log-rank test.

RESULTS AND LIMITATIONS:

Hsp90 inhibitors induced expression of HSPs in tumor cells and tissues in a dose- and time-dependent manner; in particular, Hsp27 mRNA and protein levels increased threefold. In vitro, OGX-427 synergistically enhanced Hsp90 inhibitor-induced suppression of cell growth and induced apoptosis by 60% as measured by increased sub-G1 fraction and poly(ADP-ribose) polymerase cleavage. These biologic events were accompanied by decreased expression of HSPs, Akt, AR, and prostate-specific antigen, and induction of ER stress markers (cleaved activating transcription factor 6, glucose-regulated protein 78, and DNA-damage-inducible transcript 3). In vivo, OGX-427 potentiated the anticancer effects of Hsp90 inhibitor PF-04929113 (orally, 25mg/kg) to inhibit tumor growth and prolong survival in CRPC LNCaP xenografts.

CONCLUSIONS:

HSP90 inhibitor-mediated induction of Hsp27 expression can be attenuated by OGX-427, resulting in increased ER stress and apoptosis, and synergistic inhibition of CRPC tumor growth.

PATIENT SUMMARY:

This study supports the development of targeted strategies using OGX-427 in combination with Hsp90 inhibitors to improve patient outcome in CRPC.

KEYWORDS:

Androgen receptor; Castration-resistant prostate cancer; Hsp27; Hsp90 inhibition; OGX-427

PMID:
24411988
PMCID:
PMC4079118
DOI:
10.1016/j.eururo.2013.12.019
[Indexed for MEDLINE]
Free PMC Article

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