Targeting prostate cancer with HTI-286, a synthetic analog of the marine sponge product hemiasterlin.

Abstract

Therapeutic 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.

• Authors: Boris A Hadaschik, Susan Ettinger, Richard D Sowery, Amina Zoubeidi, Raymond J Andersen, Michel Roberge, Martin E Gleave
• Journal: International journal of cancer (Int J Cancer) Vol. 122 Issue 10 Pg. 2368-76 (May 15 2008) ISSN: 1097-0215 [Electronic] United States
• PMID: 18240145 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• HTI-286
• Oligopeptides
• RNA, Messenger
• Radiation-Sensitizing Agents
• Taxoids
• Docetaxel
• hemiasterlin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Biomarkers, Tumor (genetics, metabolism)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Docetaxel
• Flow Cytometry
• Gene Expression Profiling
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasms, Hormone-Dependent (drug therapy, metabolism, pathology)
• Oligonucleotide Array Sequence Analysis
• Oligopeptides (chemistry, pharmacology)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• RNA, Messenger (genetics, metabolism)
• Radiation-Sensitizing Agents (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Taxoids (pharmacology)
• Tumor Cells, Cultured (drug effects)
• Xenograft Model Antitumor Assays