Urologic Sciences, The Vancouver Prostate Centre, Unversity of British Columbia, 2660 Oak st, Vancouver, BC, V6H 3Z6, Canada.
Small molecule inhibitors of Hsp90 show promise in the treatment of castration-resistant prostate cancer (CRPC), however these inhibitors trigger a heat shock response that attenuates drug effectiveness. Attenuation is associated with increased expression of Hsp90, Hsp70, Hsp27 and clusterin (CLU) that mediate tumor cell survival and treatment resistance. We hypothesized that preventing CLU induction in this response would enhance Hsp90 inhibitor-induced CRPC cell death in vitro and in vivo. To test this hypothesis, we treated CRPC with Hsp90 inhibitor PF-04929113 or 17-AAG in the absence or presence of OGX-011, an antisense drug that targets CLU. Treatment with either Hsp90 inhibitor alone increased nuclear translocation and transcriptional activity of the heat shock factor HSF-1, which stimulated dose- and time-dependent increases in heat shock protein expression, including especially CLU expression. Treatment-induced increases in CLU were blocked by OGX-011, which synergistically enhanced the activity of Hsp90 inhibition on CRPC cell growth and apoptosis. Accompanying these effects was a decrease in HSF-1 transcriptional activity as well as expression of HSPs, Akt, PSA and androgen receptor. In vivo evaluation of the Hsp90 inhibitors with OGX-011 in xenograft models of human CRPC demonstrated that OGX-011 markedly potentiated anti-tumor efficacy, leading to an 80% inhibition of tumor growth with prolonged survival compared to Hsp90 inhibitor monotherapy. Together, our findings indicate that Hsp90 inhibitor-induced activation of the heat shock response and CLU is attenuated by OGX-011, with synergistic effects on delaying CRPC progression.
Written by:
Lamoureux F, Thomas C, Yin MJ, Kuruma H, Beraldi E, Fazli L, Zoubeidi A, Gleave ME. Are you the author?
Reference: Cancer Res. 2011 Jul 7. Epub ahead of print.
doi: 10.1158/0008-5472.CAN-11-0994
PubMed Abstract
PMID: 21737488
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