Targeting prostate cancer with HTI‐286, a synthetic analog of the marine sponge product hemiasterlin Journal Articles uri icon

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abstract

  • AbstractTherapeutic resistance is the underlying cause for most cancer deaths and a major problem associated with treatment of metastatic prostate cancer. HTI‐286, a fully synthetic analog of the natural tripeptide hemiasterlin, inhibits tubulin polymerization and circumvents transport‐based resistance to taxanes. In our study, we evaluated its inhibitory effects on human prostate cancer growth in vitro and in different in vivo models. Androgen‐dependent and androgen‐independent prostate cancer cell lines including a docetaxel‐refractory PC‐3 subline (PC‐3dR) were treated with HTI‐286. Transcriptional profiling was carried out to screen for changes in gene expression induced by HTI‐286 and compared to docetaxel. In vivo, nude mice with established PC‐3 or PC‐3dR xenografts were given HTI‐286 intravenously. Additionally, mice bearing hormone‐sensitive LNCaP tumors were treated with castration in combination with early or delayed HTI‐286 therapy. In all cell lines tested, HTI‐286 was a potent inhibitor of proliferation and induced marked increases in apoptosis. Despite similar transcriptomic changes regarding cell death and cell cycle regulating genes after exposure to HTI‐286 or docetaxel, array analysis revealed distinct molecular signatures for both compounds. Invivo, HTI‐286 significantly inhibited growth of PC‐3 and LNCaP xenografts and retained potency in PC‐3dR tumors. Simultaneous castration plus HTI‐286 therapy was superior to sequential treatment in the LNCaP model. In conclusion, HTI‐286 showed strong antitumor activity both in androgen‐dependent and androgen‐ independent tumors and may be a promising agent in second‐ line treatment strategies for patients suffering from docetaxel‐ refractory prostate cancer. © 2008 Wiley‐Liss, Inc.

authors

  • Hadaschik, Boris A
  • Ettinger, Susan
  • Sowery, Richard
  • Zoubeidi, Amina
  • Andersen, Raymond J
  • Roberge, Michel
  • Gleave, Martin E

publication date

  • May 15, 2008

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