Clusterin inhibition using OGX-011 synergistically enhances Hsp90 inhibitor activity by suppressing the heat shock response in castrate-resistant prostate cancer.

Abstract

Small-molecule inhibitors of Hsp90 show promise in the treatment of castrate-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 the 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 HSP expression, 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, prostate-specific antigen, and androgen receptor. In vivo evaluation of the Hsp90 inhibitors with OGX-011 in xenograft models of human CRPC showed that OGX-011 markedly potentiated antitumor efficacy, leading to an 80% inhibition of tumor growth with prolonged survival compared with 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.

• Authors: Francois Lamoureux, Christian Thomas, Min-Jean Yin, Hidetoshi Kuruma, Eliana Beraldi, Ladan Fazli, Amina Zoubeidi, Martin E Gleave
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 17 Pg. 5838-49 (Sep 01 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21737488 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Benzamides
• Benzoquinones
• Clusterin
• HSP90 Heat-Shock Proteins
• Indazoles
• Lactams, Macrocyclic
• OGX-011
• Thionucleotides
• tanespimycin
• SNX-5422
• Glycine

Topics

• Animals
• Apoptosis (drug effects)
• Benzamides (therapeutic use)
• Benzoquinones (therapeutic use)
• Cell Line, Tumor
• Clusterin (antagonists & inhibitors, genetics)
• Drug Synergism
• Glycine
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Heat-Shock Response (drug effects, genetics)
• Humans
• Indazoles (therapeutic use)
• Lactams, Macrocyclic (therapeutic use)
• Male
• Mice
• Mice, Nude
• Prostatic Neoplasms (drug therapy, pathology)
• Thionucleotides (therapeutic use)
• Xenograft Model Antitumor Assays